Histone methyltransferase inhibitors

ABSTRACT

The present disclosure provides compounds of Formula (I) that are histone methyltransferases G9a and/or GLP inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of G9a and/or GLP such as cancers and hemoglobinpathies (e.g., beta thalassemia and sickle cell disease). Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds. 
                         
where R 1 , alk, R 2 , Z 1 , Z 2 , X, R 3 , R 4 , B, a, and b are as described herein.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claimis identified, for example, in the Application Data Sheet or Request asfiled with the present application, are hereby incorporated by referenceunder 37 CFR 1.57, and Rules 4.18 and 20.6.

FIELD OF THE DISCLOSURE

The present disclosure provides certain angular tricyclic compounds thatare histone methyltransferases G9a and/or GLP inhibitors, and aretherefore useful for the treatment of diseases treatable by inhibitionof G9a and/or GLP such as cancers and hemoglobinpathies (e.g.,beta-thalassemia and sickle cell disease). Also provided arepharmaceutical compositions containing such compounds and processes forpreparing such compounds.

BACKGROUND

Chromatin modification plays an essential role in transcriptionalregulation. These modifications, including DNA methylation, histoneacetylation and histone methylation, are important in a variety ofbiological processes including protein production and cellulardifferentiation, and are emerging as attractive drug targets in varioushuman diseases. Two particular enzymes associated with histonemethylation are G9a and GLP, also known as EHMT2 and EHMT1 (Euchromatichistone-lysine N-methyltransferase 2 and 1). G9a and GLP are the primaryenzymes for mono- and dimethylation at Lys 9 of histone H3 (H3K9me1 andH3K9me2), and exist predominantly as a G9a-GLP heteromeric complex thatappears to be a functional H3K9 methyltransferase in vivo. Structurally,either G9a or GLP is composed of a catalytic SET domain, a domaincontaining ankyrin repeats (involved in protein-protein interactions)and nuclear localization signals on the N-terminal region. The SETdomain is responsible for the addition of methyl groups on H3, whereasthe ankyrin repeats have been observed to represent mono- and dimethyllysine binding regions. The G9a-GLP complex is thus not only able toboth methylate histone tails but also able to recognize thismodification, and can function as a scaffold for the recruitment ofother target molecules on the chromatin [see Shinkai et al., Genes Dev.2011 Apr. 15; 25(8):781-8. doi: 10.1101/gad.2027411. H3K9methyltransferase G9a and the related molecule GLP; and Shankar et al.,Epigenetics. 2013 January; 8(1):16-22. doi:10.4161/epi.23331. G9a, amultipotent regulator of gene expression].

Many studies have reported that G9a and GLP play critical roles invarious biological processes. Several reports have highlighted its linkto a variety of cancers [see Cascielle et al., Front Immunol. 2015 Sep.25; 6:487. doi: 10.3389/fimmu.2015.00487. Functional Role of G9a HistoneMethyltransferase in Cancer]. It is upregulated in hepatocellularcarcinoma, B cell acute lymphoblastic leukemia, and lung cancers. Inaddition, elevated expression of G9a in aggressive lung cancercorrelates with poor prognosis, while its knockdown in highly invasivelung cancer cells suppressed metastasis in an in vivo mouse model. Inprostate cancer cells (PC3), G9a knockdown caused significantmorphological changes and inhibition of cell growth. [see Liu et al., J.Med Chem. 2013 Nov. 14; 56(21):8931-42. doi: 10.1021/jm401480r. Epub2013 Oct. 31. Discovery of an in vivo chemical probe of the lysinemethyltransferases G9a and GLP; and Sweis et al., ACS Med Chem Lett.2014 Jan. 2; 5(2):205-9. doi: 10.1021/m1400496h. eCollection 2014.Discovery and development of potent and selective inhibitors of histonemethyltransferase g9a.] Loss of G9a has been demonstrated to impair DNAdamage repair and enhance the sensitivity of cancer cells to radiationand chemotherapeutics. See Yang et al., Proc. Natl. Acad. Sci. USA,2017, doi: 10.1073/pnas.1700694114.

Interestingly, recent studies have also shown that the inhibition of G9aand GLP by either genetic depletion or pharmacological interventionincreased fetal hemoglobin (HbF) gene expression in erythroid cells [seeKrivega et al., Blood. 2015 Jul. 30; 126(5):665-72. Inhibition of G9amethyltransferase stimulates fetal hemoglobin production by facilitatingLCR/γ-globin looping; and Renneville et al., Blood. 2015 Oct. 15;126(16):1930-9. EHMT1 and EHMT2 inhibition induces fetal hemoglobinexpression]. Inducing fetal globin gene would be potentiallytherapeutically beneficial for the disease of hemoglobinpathies,including beta-thalassemia and sickle cell disease where the productionof normal β-globin, a component of adult hemoglobin, is impaired. [seeSankaran et al., Cold Spring Harb Perspect Med. 2013 January; 3(1):a011643. doi:10.1101/cshperspect.a011643 The Switch from Fetal to AdultHemoglobin]. Moreover, G9a or GLP inhibitions may potentiate otherclinically used therapies, such as hydroxyurea or HDAC inhibitors. Theseagents may act, at least in part, by increasing γ-globin gene expressionthrough different mechanisms [see Charache et al., Blood. 1992 May 15;79(10):2555-65. Hydroxyurea: effects on hemoglobin F production inpatients with sickle cell anemia]. Thus, there is a need for thedevelopment of small molecules that are capable of inhibiting theactivity of G9a and/or GLP. The compounds of the present disclosurefulfill this and related needs.

SUMMARY

In one aspect provided is a compound of Formula (I):

where:

Z¹ and Z² are independently C (when R² or R³ is attached thereto), CH,or N;

alk is alkylene wherein one or two carbon atoms of the alkylene chainare optionally replaced by NR, O, S, or SO₂ (where R is hydrogen oralkyl), and the alkylene chain is optionally substituted with one or twosubstituents independently selected from halo, haloalkyl, haloalkoxy,hydroxy, and alkoxy, and wherein -alk-R¹ is attached to carbon (a) or(b);

R¹ is —NR⁶R⁷ (where R⁶ and R⁷ are independently hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, or haloalkoxyalkyl), unsubstitutedheterocyclyl, heterocyclyl substituted with 1, 2, or 3 of R^(a), R^(b),and R^(c) wherein R^(a), R^(b), and R^(c) are independently selectedfrom alkyl, hydroxy, alkoxy, halo, haloalkyl, alkylcarbonyl, andhaloalkylcarbonyl, or spiroheterocycloamino wherein a nitrogen atom ofthe spiroheterocycloamino is attached to alk;

R² is hydrogen, alkyl, cycloalkyl, halo, hydroxy, alkoxy, haloalkoxy, orcyano;

R³ is hydrogen, alkyl, halo, alkoxy, alkylamino, dialkylamino, or cyano;

R⁴ is hydrogen, deuterium, alkyl (optionally substituted with one tonine deuteriums), cycloalkyl (optionally substituted with one or twosubstituents independently selected from alkyl, hydroxy, halo, alkoxy,haloalkyl, and haloalkoxy), cycloalkenyl, phenyl (optionally substitutedwith one or two substituents independently selected from alkyl, halo,hydroxy, alkoxy, haloalkyl, and haloalkoxy), heteroaryl (optionallysubstituted with one or two substituents independently selected fromalkyl, halo, hydroxy, and alkoxy), heterocyclyl (optionally substitutedwith one or two substituents independently selected from alkyl, halo,hydroxy, and alkoxy), —OR^(d) (where R^(d) is hydrogen, alkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, halocycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,or heterocyclylalkyl), or NR^(e)R^(f) (where R^(e) is hydrogen or alkyland R^(f) is hydrogen, alkyl, deuterated alkyl, alkylthioalkyl, acyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyanoalkyl,carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl),wherein the cycloalkyl, the aryl, the heteroaryl, and the heterocyclyleither alone or as part of the cycloalkylalkyl, the aralkyl, theheteroaralkyl and the heterocyclylalkyl in R^(d) and R^(f) areindependently unsubstituted or substituted with 1, 2, or 3 of R^(g),R^(h), and R^(i) wherein R^(g), R^(h), and R^(i) are independentlyselected from alkyl, hydroxy, alkoxy, halo, haloalkyl, cyano, carboxy,alkoxycarbonyl, and haloalkoxy, and wherein the alkylene of the aralkyl,the heteroaralkyl, the heterocyclylalkyl, and the cycloalkylalkyl inR^(d) and R^(f) is optionally substituted with one to nine deuteriums;

X is carbon or nitrogen; and

ring B is phenyl, 5- or 6-membered heteroaryl containing one, two, orthree heteroatoms independently selected from nitrogen, oxygen, andsulfur, 5- or 6-membered cycloalkyl, spirocycloalkyl,spiroheterocycloamino, or 5-, 6-, or 7-membered saturated heterocyclyl,wherein each of the ring(s) of ring B is unsubstituted or substitutedwith 1, 2, 3, or 4 of R^(j), R^(k), R^(l), and R^(m) wherein R^(j),R^(k), R^(l), and R^(m) are independently selected from alkyl, hydroxy,cyano, alkoxy, halo, haloalkyl, and haloalkoxy; or

a pharmaceutically acceptable salt thereof; provided the compound ofFormula (I) is not:

5-aminobenzo[f][1,7]naphthyridine-8-methanamine or

10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridin-5-ol;or

a salt thereof.

In a second aspect, this disclosure is directed to a pharmaceuticalcomposition comprising a compound of Formula (I) (or any of theembodiments thereof described herein), or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable excipient.

In a third aspect, this disclosure is directed to a method of treating adisease treatable by inhibition of G9a and/or GLP in a subject in needthereof, comprising administering a therapeutically effective amount ofa compound of Formula (I) (or any of the embodiments thereof describedherein), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising a compound of Formula (I) (or anyof the embodiments thereof described herein), or a pharmaceuticallyacceptable salt thereof, in a therapeutically effective amount, and apharmaceutically acceptable excipient. In one embodiment, the diseasecan be a hemoglobinpathy, such as beta-thalassemia and sickle celldisease. See Krivega et al., Blood, 2015; 126(5):665-72 and Rennevilleet al., Blood. 2015 Oct. 15; 126(16):1930-9. In a second embodiment, thedisease can be a cancer or tumor, for example, a cancer or tumor whereG9a or GLP can be overexpressed. Examples of such cancers and tumorsinclude, but are not limited to: Colorectal Cancer, Osteosarcoma Cancer,Acute Lymphoblastic Leukemia (ALL); Acute Myeloid Leukemia (AML);Adrenocortical Carcinoma, Kaposi Sarcoma (Soft Tissue Sarcoma);AIDS-Related Lymphoma (Lymphoma); Primary CNS Lymphoma; Anal Cancer;Gastrointestinal Carcinoid Tumors; Astrocytomas; AtypicalTeratoid/Rhabdoid Tumor; Basal Cell Carcinoma of the Skin; Bile DuctCancer; Bladder Cancer; Bone Cancer (includes Ewing Sarcoma andOsteosarcoma and Malignant Fibrous Histiocytoma); Brain Tumors; BreastCancer; Bronchial Tumors—Burkitt Lymphoma; Cardiac Tumors; EmbryonalTumors (Brain Cancer); Germ Cell Tumor (Brain Cancer); Primary CNSLymphoma; Cervical Cancer; Cholangiocarcinoma; Chordoma; ChronicLymphocytic Leukemia (CLL); Chronic Myelogenous Leukemia (CML); ChronicMyeloproliferative Neoplasms; Colorectal Cancer; Craniopharyngioma(Brain Cancer); Cutaneous T-Cell Lymphoma; Ductal Carcinoma In Situ(DCIS); Endometrial Cancer (Uterine Cancer); Ependymoma (Brain Cancer);Esophageal Cancer; Esthesioneuroblastoma; Ewing Sarcoma (Bone Cancer);Extracranial Germ Cell Tumor; Extragonadal Germ Cell Tumor; Eye Cancer;Intraocular Melanoma; Retinoblastoma; Fallopian Tube Cancer; FibrousHistiocytoma of Bone; Gallbladder Cancer; Gastric (Stomach)Gastrointestinal Stromal Tumors (GIST) (Soft Tissue Sarcoma); CNS GermCell Tumors (Brain Cancer); Extracranial Germ Cell Tumors; ExtragonadalGerm Cell Tumors; Ovarian Germ Cell Tumors; Testicular Cancer;Gestational Trophoblastic Disease; Hairy Cell Leukemia; Head and NeckCancer; Hepatocellular (Liver) Cancer; Histiocytosis, Langerhans Cell;Hodgkin Lymphoma; Hypopharyngeal Cancer (Head and Neck Cancer);Intraocular Melanoma; Islet Cell Tumors, Pancreatic NeuroendocrineTumors; Kidney (Renal Cell) Cancer; Langerhans Cell Histiocytosis;Laryngeal Cancer (Head and Neck Cancer); Leukemia; Lip and Oral CavityCancer (Head and Neck Cancer); Lung Cancer (Non-Small Cell and SmallCell); Lymphoma; Male Breast Cancer; Melanoma; Merkel Cell Carcinoma(Skin Cancer); Mesothelioma, Malignant Mesothelioma; Metastatic SquamousNeck Cancer with Occult Primary (Head and Neck Cancer); Midline TractCarcinoma Involving NUT Gene; Mouth Cancer (Head and Neck Cancer);Multiple Endocrine Neoplasia Syndromes; Multiple Myeloma/Plasma CellNeoplasms; Mycosis Fungoides (Lymphoma); Myelodysplastic Syndromes,Myelodysplastic/Myeloproliferative Neoplasms; Myelogenous Leukemia,Chronic (CML); Myeloproliferative Neoplasms, Chronic; Nasal Cavity andParanasal Sinus Cancer (Head and Neck Cancer); Nasopharyngeal Cancer(Head and Neck Cancer); Nasopharyngeal Cancer—Neuroblastoma; Non-HodgkinLymphoma; Oral Cancer; Lip and Oral Cavity Cancer and OropharyngealCancer (Head and Neck Cancer); Ovarian Cancer; Pancreatic Cancer;Papillomatosis; Paraganglioma; Paranasal Sinus and Nasal Cavity Cancer(Head and Neck Cancer); Parathyroid Cancer; Penile Cancer; PharyngealCancer (Head and Neck Cancer); Pheochromocytoma; Pituitary Tumor; PlasmaCell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy andBreast Cancer; Primary CNS Lymphoma; Primary Peritoneal Cancer; ProstateCancer; Rectal Cancer; Recurrent Cancer; Rhabdomyosarcoma (Soft TissueSarcoma); Salivary Gland Cancer (Head and Neck Cancer); Salivary GlandTumors; Vascular Tumors (Soft Tissue Sarcoma); Uterine Sarcoma; SézarySyndrome (Lymphoma); Small Intestine Cancer; Soft Tissue Sarcoma;Squamous Cell Carcinoma of the Skin; Skin Cancer; Squamous Neck Cancerwith Occult Primary, Metastatic (Head and Neck Cancer); T-Cell Lymphoma,Cutaneous; Lymphoma (Mycosis Fungoides and Sézary Syndrome); ThroatCancer (Head and Neck Cancer); Nasopharyngeal Cancer; OropharyngealCancer; Hypopharyngeal Cancer; Thymoma and Thymic Carcinoma; ThyroidCancer; Urethral Cancer; Vaginal Cancer; Vascular Tumors (Soft TissueSarcoma); Vulvar Cancer; Myelodysplastic syndrome (MDS); and WilmsTumor. Thus, the terms “cancerous cell,” “cancer cell” or “tumor cell”as provided herein, includes a cell afflicted by any one of or relatedto the above identified conditions. See Cascielle et al., Front.Immunol. 2015; 6:487, Agarwal et al., Cancer Letters 2016: 467 and Zhanget al., Oncotarget 2015, 6(5): 2917. In a third embodiment, treating acancer and/or tumor comprises increasing tumor free survival and/orreducing tumor mass and/or slowing tumor growth. In a fourth embodiment,the disease can be a cancer predisposition syndrome, such as Cowdensyndrome. See You et al., Cancer Cell, 2012; 22(1):9-20. In a fifthembodiment, the disease can be an inflammatory and/or autoimmunedisease, such as intestinal inflammation, arthritis, atherosclerosis,multiple sclerosis, myasthenia gravis, Crohn's disease,graft-versus-host disease, psoriasis, granulomatous colitis, lymphocytecolitis, collagenous colitis, ulcerative colitis, Coeliac Disease,subepidermal blistering disorders, systemic lupus erythematosus, discoidlupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis,Sjogren's syndrome, primary biliary cirrhosis, active chronic hepatitis,chronic fatigue syndrome and vasculitis. See Antignano et al., J. Clin.Invest. 2014 4(5): 1945-55. In a sixth embodiment, the disease can be ametabolic disease, such as diabetes and/or obesity. See Wang et al.,EMBO J. 2013; 32(1):45-59. In a seventh embodiment, the disease can berelated to skeletal muscle development and regeneration. See Ling etal., Proc. Natl. Acad. Sci. USA, 2012; 109(3):841-6. In an eighthembodiment, the disease can be a viral disease, such as HIV-1 (humanimmunodeficiency virus 1) and HBV (Hepatitis B Virus). See Imai et al.,J. Biol. Chem. 2010; 285(22):16538-45 and Merkling et al., PLoS Pathog.2015; 11(4). The compounds and compositions described herein can beadministered with one or more additional therapeutic agents including,but not limited to, anticancer agents and antiviral agents. See, e.g.,Front Immunol. 2015; 6:487; Agarwal et al., Cancer Lett. 2016:467 andZhang et al., Oncotarget 2015, 6(5):2917.

In a fourth aspect provided is the use of a compound of Formula (I) (orany of the embodiments thereof described herein), or a pharmaceuticallyacceptable salt thereof, in the treatment of the diseases provided inthe third aspect herein.

In a fifth aspect, this disclosure is directed to a method of inhibitingG9a and/or GLP, comprising contacting a cell with a therapeuticallyeffective amount of a compound of Formula (I) (or any of the embodimentsthereof described herein), or a pharmaceutically acceptable saltthereof. In some embodiments, the cell suffers from one or more of thediseases provided in the third aspect herein.

DETAILED DESCRIPTION Definitions

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meaning:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, n-propyl,2-propyl (isopropyl), n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl(straight-chained or branched), hexyl (straight-chained or branched),and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms unless otherwise stated, e.g., methylene,ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene,pentylene, and the like.

“Alkylthioalkyl” means a —RSR′ radical where R and R′ are independentlyan alkyl as defined above.

“Alkoxy” means a —OR radical where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, andthe like.

“Alkoxyalkyl” means alkyl as defined above which is substituted with oneor two alkoxy groups as defined above, e.g., methoxyethyl, ethoxyethyl,methoxypropyl, and the like.

“Alkylcarbonyl” or “Acyl” means a —COR radical where R is alkyl asdefined above, e.g., methylcarbonyl, ethylcarbonyl, and the like.

“Alkoxycarbonyl” means a —C(═O)OR radical where —R is alkyl as definedabove, e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, andthe like.

“Alkoxycarbonylalkyl” means alkyl as defined above which is substitutedwith one or two alkoxycarbonyl groups as defined above, e.g.,methoxycarbonylethyl, ethoxycarbonylethyl, methoxycarbonylpropyl, andthe like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms, e.g., phenyl or naphthyl.

“Aralkyl” means a -(alkylene)-R radical where R is aryl as definedabove, e.g., benzyl, phenethyl, and the like.

“Aminoalkyl” means a -(alkylene)-NR′R″ radical where R′ and R″ areindependently hydrogen or alkyl as defined above.

“Alkylamino” means a —NHR′ radical where R′ is alkyl as defined above.

“Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical ofthree to ten carbon atoms, unless stated otherwise, e.g., cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, and the like.

“Cycloalkylalkyl” means a -(alkylene)-R radical where R is cycloalkyl asdefined above, e.g., cyclopropylmethyl, cyclohexylmethyl, and the like.

“Cycloalkenyl” means a cyclic hydrocarbon radical of three to ten carbonatoms containing a double bond, unless stated otherwise, e.g.,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

“Cyanoalkyl” means an alkyl radical as defined above that is substitutedwith a cyano group.

“Carboxy” means a —C(═O)OH group.

“Carboxyalkyl” means an alkyl radical as defined above that issubstituted with a carboxy group.

“5- or 6-Membered cycloalkenyl” means a cyclic hydrocarbon radical offive or six carbon atoms containing a double bond.

“Deuterated alkyl” means an alkyl radical as defined above that issubstituted with one, two or three deuterium atoms.

“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as definedabove.

“Halo” or “halogen” means fluoro, chloro, bromo, or iodo, preferablyfluoro or chloro.

“Haloalkyl” means an alkyl radical as defined above, which issubstituted with one or more halogen atoms, such as one to five halogenatoms, such as fluorine or chlorine, including those substituted withdifferent halogens, e.g., —CH₂Cl, —CF₃, —CHF₂, —CH₂CF₃, —CF₂CF₃,—CF(CH₃)₂, and the like. When the alkyl is substituted with only fluoro,it can be referred to in this Application as fluoroalkyl.

“Haloalkoxy” means a —OR radical where R is haloalkyl as defined above,e.g., —OCF₃, —OCHF₂, —OCH₂F, and the like. When the haloalkyl of ahaloalkoxy is an alkyl substituted with only fluoro, the haloalkoxy isreferred to in this Application as fluoroalkoxy.

“Haloalkoxyalkyl” means alkyl as defined above which is substituted withone or two haloalkoxy groups as defined above, e.g.,trifluormethoxyethyl, 2,2,2-trifluoroethoxyethyl, and the like.

“Haloalkylcarbonyl” means a —COR radical where R is haloalkyl as definedabove, e.g., trifluoromethylcarbonyl, pentafluoroethylcarbonyl, and thelike.

“Hydroxyalkyl” means alkyl as defined above which is substituted withone or two hydroxy groups as defined above, e.g., hydroxyethyl,hydroxyethyl, 1,3-dihydroxypropyl, and the like.

“Halocycloalkyl” means cycloalkyl group as defined above which issubstituted with one, two or three halogen as defined above, e.g.,2,2-difluorocyclopropyl, and the like.

“Heterocyclyl” means a saturated or unsaturated monovalent monocyclicgroup of 4 to 8 ring atoms in which one or two ring atoms are heteroatomindependently selected from N, O, and S(O)_(n), where n is an integerfrom 0 to 2, and the remaining ring atoms are C, unless statedotherwise. Additionally, one or two ring carbon atoms in theheterocyclyl ring can optionally be replaced by a —C(═O)— group. Morespecifically the term heterocyclyl includes, but is not limited to,pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl,2-oxopiperidinyl, morpholino, piperazino, dihydropyranyl,thiomorpholino, and the like. When the heterocyclyl ring is unsaturatedit can contain one or two ring double bonds provided that the ring isnot aromatic. When the heterocyclyl group contains at least one nitrogenatom (e.g., pyrrolidine, piperidine, piperazine, and oxazolidine), theheterocyclyl ring can also be referred to herein as heterocycloamino andis a subset of the heterocyclyl group. When the heterocyclyl ring has nodouble bond, it is referred to herein as saturated heterocyclyl.

“Heterocyclylalkyl” or “heterocycloalkyl” means a -(alkylene)-R radicalwhere R is heterocyclyl ring as defined above, e.g.,tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and thelike.

“5-, 6-, or 7-Membered heterocycloalkenyl or heterocyclylalkenyl” meansa cyclic hydrocarbon radical of five, six, or seven carbon atomscontaining a double bond and wherein one or two carbon atoms areindependently replaced by N, O, or S(O). where n is an integer from 0 to2.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms, unless otherwise stated, where one or more, (inone embodiment, one, two, or three), ring atoms are heteroatom selectedfrom N, O, and S, the remaining ring atoms being carbon. Representativeexamples include, but are not limited to, pyrrolyl, thienyl, thiazolyl,imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl,benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and thelike. When the heteroaryl ring contains 5- or 6 ring atoms, it is alsoreferred to herein as 5- or 6-membered heteroaryl.

“Heteroaralkyl” means a -(alkylene)-R radical where R is heteroaryl asdefined above, e.g., pyridinylmethyl, and the like. When the heteroarylring in heteroaralkyl contains 5 or 6 ring atoms, the heteroaralkyl isalso referred to herein as 5- or 6-membered heteroaralkyl.

“Oxo” means a ═(O) radical. As would be readily apparent to one of skillin the art, “carbonyl” refers to an oxo radical attached to a carbonatom, i.e., —C(═O)—.

“Spiroheterocycloamino” means a saturated bicyclic ring having 7 to 10ring atoms in which one, two, or three ring atoms are heteroatomselected from N, N-oxide, O, and S(O)_(n), where n is an integer from 0to 2, the remaining ring atoms being C, provided that at least one ringatom is N, and the rings are connected through only one atom. Theconnecting atom is also called the spiroatom, and is most often aquaternary carbon (“spiro carbon”).

“Spirocycloalkyl” means a saturated bicyclic ring having 7 to 10 carbonring atoms wherein the rings are connected through only one atom. Theconnecting atom is also called the spiroatom, and is most often aquaternary carbon (“spiro carbon”).

It will be well recognized by a person skilled in the art that when ringB is cycloalkyl, heterocyclyl, or spirocycloalkyl, the carbon atoms inthese rings that are shared with the adjacent ring (i.e., ringsubstituted with R⁴ in Formula I) are sp² carbons.

The present disclosure also includes protected derivatives of compoundsof the present disclosure. For example, when compounds of the presentdisclosure contain groups such as hydroxy, carboxy, thiol or any groupcontaining a nitrogen atom(s), these groups can be protected with asuitable protecting group. A comprehensive list of suitable protectivegroups can be found in T. W. Greene, Protective Groups in OrganicSynthesis, John Wiley & Sons, Inc. (1999), the disclosure of which isincorporated herein by reference in its entirety. The protectedderivatives of compounds of the present disclosure can be prepared bymethods well known in the art.

The present disclosure also includes polymorphic forms and deuteratedforms of the compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as formic acid, acetic acid,propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. It is understood that thepharmaceutically acceptable salts are non-toxic. Additional informationon suitable pharmaceutically acceptable salts can be found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, which is incorporated herein by reference in itsentirety.

The compounds of the present disclosure may have asymmetric centers.Compounds of the present disclosure containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of materials. All chiral, diastereomeric, all mixturesof chiral or diastereomeric forms, and racemic forms are within thescope of this disclosure, unless the specific stereochemistry orisomeric form is specifically indicated. It will also be understood by aperson of ordinary skill in the art that when a compound is denoted as(R) stereoisomer, it may contain the corresponding (S) stereoisomer asan impurity, i.e., the (S) stereoisomer in less than about 5%,preferably 2% by wt. and then it is denoted as a mixture of R and Sisomers, the amounts of R or S isomer in the mixture is greater thanabout 5%, preferably 2% w/w.

Certain compounds of the present disclosure can exist as tautomersand/or geometric isomers. All possible tautomers and cis and transisomers, as individual forms and mixtures thereof are within the scopeof this disclosure. Additionally, as used herein the term alkyl includesall the possible isomeric forms of said alkyl group albeit only a fewexamples are set forth. Furthermore, when the cyclic groups such asaryl, heteroaryl, heterocyclyl are substituted, they include all thepositional isomers albeit only a few examples are set forth.Furthermore, all hydrates of a compound of the present disclosure arewithin the scope of this disclosure.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocyclyl group optionallysubstituted with an alkyl group” means that the alkyl may but need notbe present, and the description includes situations where theheterocyclyl group is substituted with an alkyl group and situationswhere the heterocyclyl group is not substituted with alkyl.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogen.

Also provided herein are isotopologues (isotopically labeled analogues)of the compounds described herein. Substitution with isotopes such asdeuterium may afford certain therapeutic advantages resulting fromgreater metabolic stability, such as, for example, increased in vivohalf-life or reduced dosage requirements. In some embodiments, at anyposition of a compound described herein, or a pharmaceuticallyacceptable salt thereof, that has a hydrogen, the hydrogen atom can bereplaced with hydrogen-2 (deuterium) or hydrogen-3 (tritium).

A “pharmaceutically acceptable carrier or excipient” means a carrier oran excipient that is useful in preparing a pharmaceutical compositionthat is generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes a carrier or an excipient that is acceptablefor veterinary use as well as human pharmaceutical use. “Apharmaceutically acceptable carrier/excipient” as used in thespecification and claims includes both one and more than one suchexcipient.

A “subject” refers to an animal that is the object of treatment,observation or experiment. “Animal” includes cold- and warm-bloodedvertebrates and invertebrates such as fish, shellfish, reptiles and, inparticular, mammals. “Mammal” includes, without limitation, mice, rats,rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates,such as monkeys, chimpanzees and apes, and, in particular, humans. Insome embodiments, the subject can be human. In some embodiments, thesubject can be a child and/or an infant, for example, a child or infantwith a fever. In other embodiments, the subject can be an adult.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e., causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease;

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms; or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

A “therapeutically effective amount” means the amount of a compound ofthe present disclosure or a pharmaceutically acceptable salt thereofthat, when administered to a subject for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the subjectto be treated.

Embodiments

In further embodiments 1-54 below, the present disclosure includes:

1. In embodiment 1, the compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, are as defined in the Summary.

2. In embodiment 2, the compounds of embodiment 1, or a pharmaceuticallyacceptable salt thereof, are those wherein ring B is phenyl or phenylsubstituted with 1, 2, 3, or 4 of R^(j), R^(k), R^(l), and R^(m) whereinR^(j), R^(k), R^(l), and R^(m) are independently selected from alkyl,hydroxy, alkoxy, halo, haloalkyl, and haloalkoxy. Within embodiment 2,in one group of compounds, or a pharmaceutically acceptable saltthereof, ring B is phenyl substituted with 1, 2, 3, or 4 of R^(j),R^(k), R^(l), and R^(m) wherein R^(j), R^(k), R^(l), and R^(m) areindependently selected from methyl, ethyl, fluoro, chloro, methoxy,trifluoromethyl, and trifluoromethoxy. Within embodiment 2, in anothergroup of compounds, or a pharmaceutically acceptable salt thereof, ringB is phenyl.3. In embodiment 3, the compounds of embodiment 1, or a pharmaceuticallyacceptable salt thereof, are those wherein ring B is an unsubstituted 5-or 6-membered cycloalkyl or a 5- or 6-membered cycloalkyl substitutedwith 1, 2, 3, or 4 of R^(j), R^(k), R^(l), and R^(m) wherein R^(j),R^(k), R^(l), and R^(m) are independently selected from alkyl, hydroxy,alkoxy, halo, haloalkyl, and haloalkoxy. Within embodiment 3, ring B iscyclopentyl, cyclohexyl, cyclopentyl substituted with 1 or 2 of R^(j)and R^(k) wherein R^(j) and R^(k) are independently selected fromfluoro, hydroxy, and methyl, or cyclohexyl substituted with 1 or 2 ofR^(j) and R^(k) wherein R^(j) and R^(k) are independently selected fromfluoro, hydroxy, and methyl. Within embodiment 3, in one group ofcompounds, or a pharmaceutically acceptable salt thereof, ring B is

unsubstituted or substituted with 1, 2, 3, or 4 of R^(j), R^(k), R^(l),and R^(m) wherein R^(j), R^(k), R^(l), and R^(m) are independentlyselected from alkyl, hydroxy, alkoxy, halo, haloalkyl, and haloalkoxy.Within embodiment 3, in another group of compounds, or apharmaceutically acceptable salt thereof, ring B is

unsubstituted or substituted with 1 or 2 of R^(j) and R^(k) whereinR^(j) and R^(k) are independently selected from fluoro, hydroxy, andmethyl. Within embodiment 3, in yet another group of compounds, or apharmaceutically acceptable salt thereof, ring B is

unsubstituted or substituted with one or two methyl groups. Withinembodiment 3, in yet another group of compounds, or a pharmaceuticallyacceptable salt thereof, ring B is:

preferably

4. In embodiment 4, the compounds of embodiment 1, or a pharmaceuticallyacceptable salt thereof, are those wherein ring B is an unsubstituted5-, 6- or 7-membered saturated heterocyclyl or a 5-, 6- or 7-memberedsaturated heterocyclyl substituted with 1, 2, 3, or 4 of R^(j), R^(k),R^(l), and R^(m) wherein R^(j), R^(k), R^(l), and R^(m) areindependently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, andhaloalkoxy. Within embodiment 4 in yet another group of compounds, or apharmaceutically acceptable salt thereof, ring B is:

each ring is unsubstituted or substituted with 1, 2, 3, or 4 of R^(j),R^(k), R^(l), and R^(m) wherein R^(j), R^(k), R^(l), and R^(m) areindependently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, andhaloalkoxy. Within embodiment 4, in another one group of compounds, or apharmaceutically acceptable salt thereof,

ring B is

each ring is unsubstituted or substituted with 1 or 2 of R^(j) and R^(k)wherein R^(j) and R^(k) are independently selected from fluoro, chloro,hydroxy, and methyl. Within embodiment 4, in yet another group ofcompounds or a pharmaceutically acceptable salt thereof, ring B is:

each ring is unsubstituted or substituted with one or two methyl groups.Within embodiment 4, in yet another group of compounds, or apharmaceutically acceptable salt thereof, ring B is:

each ring is unsubstituted or substituted with one to four methylgroups. Within embodiment 4, in yet another group of compounds, or apharmaceutically acceptable salt thereof, ring B is:

5. In embodiment 5, the compounds of embodiment 1, or a pharmaceuticallyacceptable salt thereof, are those wherein ring B is an unsubstituted 5-or 6-membered heteroaryl or a 5- or 6-membered heteroaryl substitutedwith 1, 2, 3, or 4 of R^(j), R^(k), R^(l), and R^(m) wherein R^(j),R^(k), R^(l), and R^(m) are independently selected from alkyl, hydroxy,alkoxy, halo, haloalkyl, and haloalkoxy. Within embodiment 5, in onegroup of compounds, or a pharmaceutically acceptable salt thereof, ringB is pyridinyl, pyrazolyl, triazolyl, oxazolyl, or isoxazolyl eitherunsubstituted or substituted with 1, 2, 3, or 4 of R^(j), R^(k), R^(l),and R^(m) wherein R^(j), R^(k), R^(l), and R^(m) are independentlyselected from alkyl, hydroxy, alkoxy, halo, haloalkyl, and haloalkoxy.Within embodiment 5, in another one group of compounds, or apharmaceutically acceptable salt thereof, ring B is pyridinyl,pyrazolyl, triazolyl, oxazolyl, or isoxazolyl either unsubstituted orsubstituted with 1 or 2 of R^(j) and R^(k) wherein R^(j) and R^(k) areindependently selected from fluoro, chloro, hydroxy, and methyl. Withinembodiment 5, in yet another group of compounds, or a pharmaceuticallyacceptable salt thereof, ring B is pyridinyl, pyrazolyl, triazolyl,oxazolyl, or isoxazolyl either unsubstituted or substituted with one ortwo methyl groups. Within embodiment 5, in yet another group ofcompounds, or a pharmaceutically acceptable salt thereof, ring B ispyridinyl, pyrazolyl, triazolyl, oxazolyl, or isoxazolyl, preferably

6. In embodiment 6, the compounds of embodiment 1, or a pharmaceuticallyacceptable salt thereof, are those wherein ring B is a spirocycloalkylor a spiroheterocycloamino, wherein each of the rings is unsubstitutedor substituted with 1, 2, 3, or 4 of R^(j), R^(k), R^(l), and R^(m)wherein R^(j), R^(k), R^(l), and R^(m) are independently selected fromalkyl, hydroxy, alkoxy, halo, haloalkyl, and haloalkoxy. Withinembodiment 6, in a group of compounds, or a pharmaceutically acceptablesalt thereof, are those wherein ring B is a spirocycloalkyl wherein eachof the rings is unsubstituted or substituted with 1, 2, 3, or 4 ofR^(j), R^(k), R^(l), and R^(m) wherein R^(j), R^(k), R^(l), and R^(m)are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl,and haloalkoxy. Within embodiment 6, in one group of compounds, or apharmaceutically acceptable salt thereof, ring B is:

each ring is unsubstituted or substituted with 1, 2, 3, or 4 of R^(j),R^(k), R^(l), and R^(m) wherein R^(j), R^(k), R^(l), and R^(m) areindependently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, andhaloalkoxy. Within embodiment 6, in a group of compounds, or apharmaceutically acceptable salt thereof, are those wherein ring B is aspiroheterocycloamino, wherein each of the rings is unsubstituted orsubstituted with 1, 2, 3, or 4 of R^(j), R^(k), R^(l), and R^(m) whereinR^(j), R^(k), R^(l), and R^(m) are independently selected from alkyl,hydroxy, alkoxy, halo, haloalkyl, and haloalkoxy.7. In embodiment 7, the compounds of any one of embodiments 1 to 6 andgroups contained therein, or a pharmaceutically acceptable salt thereof,are those wherein Z¹ and Z² are independently C or CH. Within the groupsof compounds in embodiment 7 in one group of compounds, or apharmaceutically acceptable salt thereof, Z¹ and Z² are each CH. Withinthe groups of compounds in embodiment 7, or a pharmaceuticallyacceptable salt thereof, in one another group of compounds, Z¹ and Z²are each CH and -alk-R¹ is attached to carbon (a) in Formula (I). Withinthe groups of compounds in embodiment 7, or a pharmaceuticallyacceptable salt thereof, in yet another group of compounds Z¹ and Z² areeach CH and -alk-R¹ is attached to carbon (a), and R² is attached tocarbon (b) in Formula (I).8. In embodiment 8, the compounds of any one of embodiments 1 to 6 andgroups contained therein, or a pharmaceutically acceptable salt thereof,are those wherein one of Z¹ and Z² is N and the other is C or CH. Inembodiment 8, in another group of compounds, the compounds of any one ofembodiments 1 to 6 and groups contained therein, or a pharmaceuticallyacceptable salt thereof, are those wherein Z¹ and Z² are each N(nitrogen). Within the groups of compounds in embodiment 8, or apharmaceutically acceptable salt thereof, in one another group ofcompounds, -alk-R¹ is attached to carbon (a) in Formula (I). Within thegroups of compounds in embodiment 8, or a pharmaceutically acceptablesalt thereof, in another group of compounds or a pharmaceuticallyacceptable salt thereof, -alk-R¹ is attached to carbon (a), and R² isattached to carbon (b) in Formula (I).9. In embodiment 9, the compounds of any one of embodiments 1 to 8 andgroups contained therein, or a pharmaceutically acceptable salt thereof,are those wherein alk in -(alk)-R¹ is —(CH₂)₂—*, —(CH₂)₃—*, —(CH₂)₄—*,—CH₂CH(CH₃)CH₂—*, *—CH₂CH(CH₃)CH₂—, —O—(CH₂)—*, —O—(CH₂)₂—*,—O—(CH₂)₃—*, —OCH₂CH(CH₃)CH₂—*—OCH₂CH(F)CH₂—*, —OCH₂CH(OCH₃)CH₂—* or—OCH₂CH(OCF₃)CH₂—*, preferably alk is —(CH₂)₂—*, —(CH₂)₃—*, —(CH₂)₄—*,—CH₂CH(CH₃)CH₂—*, —O—(CH₂)₂—*, or —O—(CH₂)₃—*, more preferably alk is—O—(CH₂)₃—*, wherein the * indicates the point of attachment to —R¹.Within embodiment 9, in one group of compounds, or a pharmaceuticallyacceptable salt thereof, R¹ is —NR⁶R⁷ where —NR⁶R⁷ is amino,methylamino, ethylamino, dimethylamino, or diethylamino. Withinembodiment 9, or a pharmaceutically acceptably salt thereof, R¹ is anunsubstituted heterocyclyl. Within embodiment 9, or a pharmaceuticallyacceptable salt thereof, in another group of compounds, or apharmaceutically acceptable salt thereof, R¹ is heterocyclyl substitutedwith 1, 2, or 3 of R^(a), R^(b), and R^(c) wherein R^(a), R^(b), andR^(c) are independently selected from alkyl, hydroxy, alkoxy, and halo.Preferably, R¹ is a saturated heterocyclyl such as azetidin-1-yl,pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, ortetrahydrofuranyl, and each heterocyclyl is unsubstituted or substitutedwith 1 or 2 of R^(a) and R^(b) wherein R^(a) and R^(b) are independentlyselected from methyl, hydroxy, methoxy, and fluoro. Within embodiment 9,in another group of compounds, or a pharmaceutically acceptable saltthereof, -alk-R¹ is —O—(CH₂)₃-pyrrolidin-1-yl, —O—(CH₂)₃-piperidin-1-yl,or —O—(CH₂)₃-morpholin-4-yl wherein the pyrrolidin-1-yl, piperidin-1-yland morpholin-4-yl of —O—(CH₂)₃-pyrrolidin-1-yl,—O—(CH₂)₃-piperidin-1-yl, and —O—(CH₂)₃-morpholin-4-yl are unsubstitutedor substituted with 1 or 2 of R^(a) and R^(b) wherein R^(a) and R^(b)are independently selected from methyl, hydroxy, methoxy, and fluoro.Within embodiment 9, in yet another group of compounds, or apharmaceutically acceptable salt thereof, -alk-R¹ is —O—(CH₂)₃—R¹ whereR¹ is pyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl,3-hydroxy-3-methylazetidin-1-yl, 3-fluoroazetidinyl,3-fluoropyrrolidinyl, 3(R)-fluoropyrrolidinyl, 3(S)-fluoropyrrolidinyl,or 3,3-dimethylpyrrodin-1-yl, preferably pyrrolidin-1-yl. In embodiment9, the compounds of any one of embodiments 1 to 8 and groups containedtherein, or a pharmaceutically acceptable salt thereof, are thosewherein -alk-R¹ is —O—(CH₂)—R¹ where R¹ is 1-methylpyrrolidin-3-yl or1-methylpiperidin-3-yl.10. In embodiment 10, the compounds of any one of embodiments 1 to 9 andgroups contained therein, or a pharmaceutically acceptable salt thereof,are those wherein R² is alkyl, halo, hydroxy, or alkoxy. Withinembodiment 10, in one group of compounds, or a pharmaceuticallyacceptable salt thereof, R² is alkyl, halo or alkoxy. Within embodiment10, in another group of compounds, or a pharmaceutically acceptable saltthereof, R² is alkoxy, preferably methoxy or ethoxy. Within embodiment10, in one group of compounds, or a pharmaceutically acceptable saltthereof, R² is halo, preferably chloro or fluoro. Within embodiment 10,in one group of compounds, or a pharmaceutically acceptable saltthereof, R² is alkyl, preferably methyl or ethyl.11. In embodiment 11, the compounds of any one of embodiments 1 to 10and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein R⁴ is hydrogen.12. In embodiment 12, the compounds of any one of embodiments 1 to 10and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein R⁴ is alkyl, preferably methyl or isopropyl.13. In embodiment 13, the compounds of any one of embodiments 1 to 10and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein R⁴ is —OR^(d) (where R^(d) is hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl), wherein thecycloalkyl, the aryl, the heteroaryl, and the heterocyclyl either aloneor as part of the cycloalkylalkyl, the aralkyl, the heteroaralkyl andthe heterocyclylalkyl in R^(d) is unsubstituted or substituted with 1,2, or 3 of R^(g), R^(h), and R^(i) wherein R^(g), R^(h), and R^(i) areindependently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl,cyano, and haloalkoxy. Within embodiment 13, in one group of compounds,or a pharmaceutically acceptable salt thereof, R⁴ is —O-alkyl,preferably R⁴ is methoxy, ethoxy, or n-propoxy, or isopropoxy. Withinembodiment 13, in another group of compounds, or a pharmaceuticallyacceptable salt thereof, R⁴ is —O-cycloalkyl, preferably R⁴ iscyclopropoxy, cyclopentoxy, or cyclohexyloxy. Within embodiment 13, inyet another group of compounds, or a pharmaceutically acceptable saltthereof, R⁴ is —O-heterocyclyl unsubstituted or substituted with 1, 2,or 3 of R^(g), R^(h), and R^(i) wherein R^(g), R^(h), and R^(i) areindependently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, andhaloalkoxy, preferably R⁴ is piperidin-4-yloxy, tetrahydropyran-4-yloxy,tetrahydrofuran-3-yloxy, or 1-alkylpiperidin-4-yloxy. Within embodiment13, in one group of compounds, or a pharmaceutically acceptable saltthereof, R⁴ is hydroxy.14. In embodiment 14, the compounds of any one of embodiments 1 to 10and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein R⁴ is NR^(e)R^(f) (where R^(e) is hydrogen oralkyl, and R^(f) is hydrogen, alkyl, cyanoalkyl, carboxyalkyl,alkoxycarbonlyalkyl, deuterated alkyl, alkylthioalkyl, acyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, orheterocyclylalkyl) wherein the cycloalkyl, the aryl, the heteroaryl, andthe heterocyclyl either alone or as part of the cycloalkylalkyl, thearalkyl, the heteroaralkyl and the heterocyclylalkyl in R^(f) isunsubstituted or substituted with 1, 2, or 3 of R^(g), R^(h), and R^(i)wherein R^(g), R^(h), and R^(i) are independently selected from alkyl,hydroxy, alkoxy, halo, haloalkyl, cyano, carboxy, alkoxycarbonyl, andhaloalkoxy. Within embodiment 14, in one group of compounds, or apharmaceutically acceptable salt thereof, R⁴ is NR^(e)R^(f) (where R^(e)is hydrogen or alkyl, and R^(f) is alkyl, cyanoalkyl, carboxyalkyl,alkoxycarbonylalkyl, deuterated alkyl, alkylthioalkyl, hydroxyalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, or heterocyclylalkyl) wherein the cycloalkyl, the aryl,the heteroaryl, and the heterocyclyl either alone or as part of thecycloalkylalkyl, the aralkyl, the heteroaralkyl and theheterocyclylalkyl in R^(f) is unsubstituted or substituted with 1, 2, or3 of R^(g), R^(h), and R^(i) wherein R^(g), R^(h), and R^(i) areindependently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl,cyano, carboxy, alkoxycarbonyl, and haloalkoxy. Within embodiment 14, inanother group of compounds, or a pharmaceutically acceptable saltthereof, R⁴ is —NR^(e)-alkyl, preferably R⁴ is —NH-alkyl or—N(alkyl)-alkyl, preferably R⁴ is —NH-methyl, —NH-ethyl, —NH-n-propyl,—NH-isopropyl, —N(methyl)(isopropyl), —NH-n-butyl, —NH-isobutyl,—NH-tert-butyl, —NH—*CH(CH₃)CH₂CH₃ (where *C is (R) or (S)), orNH-pentyl (all isomers) more preferably —NH-methyl, —NH-ethyl,—NH-n-propyl, or —NH-isopropyl. Within embodiment 14, in another groupof compounds, or a pharmaceutically acceptable salt thereof, R⁴ is—NR^(e)-cyanoalkyl, preferably R⁴ is —NH—(CH₂)₂—CN or —NH—(CH₂)₃—CN.Within embodiment 14, in another group of compounds, or apharmaceutically acceptable salt thereof, R⁴ is —NR^(e)-carboxyalkyl,preferably R⁴ is —NH—(CH)—C(═O)OH. Within embodiment 14, in anothergroup of compounds, or a pharmaceutically acceptable salt thereof, R⁴ is—NR^(e)-alkoxycarbonylalkyl, preferably R⁴ is —NH—(CH)—C(═O)—(CH₂)—CH₃.Within embodiment 14, in another group of compounds, or apharmaceutically acceptable salt thereof, R⁴ is —NR^(e)-(deteratedalkyl), preferably R⁴ is —NH—CD(CH₃)₂ (where D is deuterium). Withinembodiment 14, in another group of compounds, or a pharmaceuticallyacceptable salt thereof, R⁴ is —NR^(e)-alkylthioalkyl, preferably R⁴ is—NH—(CH₂)₂—S—CH₃. Within embodiment 14, in another group of compounds,or a pharmaceutically acceptable salt thereof, R⁴ is —NR^(e)-cycloalkyl,wherein the cycloalkyl is either unsubstituted or substituted with oneor two of R^(g) or R^(h) wherein R^(g) and R^(h) are independentlyselected from alkyl, hydroxy, alkoxy, cyano, carboxy, carboxycarbonyl,halo, haloalkyl, and haloalkoxy, preferably R⁴ is —NH-cyclopropyl,—NH(1-methylcyclopropyl), —NH(1-cyanocyclopropyl),—NH(2-cyanocyclopropyl), —NH(1-carboxycyclopropyl),—NH(1-[ethoxycarbonyl]cyclopropyl), —NH-cyclobutyl,—NH(3-hydroxycyclobutyl), —NH-cyclopentyl, —N(methyl)(cyclopentyl),—NH-cyclohexyl, —NH-(3-fluorocyclobutyl), —NH-(3,3-difluorocyclobutyl),or —NH-(3,3-dimethylcyclobutyl), more preferably —NH-cyclopropyl,NH-cyclopentyl, or NH-cyclohexyl. Within embodiment 14, in another groupof compounds or a pharmaceutically acceptable salt thereof, R⁴ is:

Within embodiment 14, in another group of compounds, or apharmaceutically acceptable salt thereof, R⁴ is —NH-heterocyclyl,wherein the heterocyclyl is unsubstituted or substituted with 1, 2, or 3of R^(g), R^(h), and R^(i) wherein R^(g), R^(h), and R^(i) areindependently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, andhaloalkoxy, preferably R⁴ is —NH-piperidin-4-yl,—NH-tetrahydropyran-4-yl, —NH-oxetan-3-yl, —NH-tetrahydrofuran-3-yl,—NH-(2,6-dimethyltetrahydropyran-4-yl), or —NH-(1-alkylpiperidin-4-yl).Within embodiment 14, in another group of compounds, or apharmaceutically acceptable salt thereof, R⁴ is —NH-cycloalkylalkyl,wherein the cycloalkyl of the cycloalkylalkyl is unsubstituted orsubstituted with 1 or 2 of R^(g) and R^(h) wherein R^(g) and R^(h) areindependently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, andhaloalkoxy, preferably R⁴ is —NH—CH₂-cycloalkyl, wherein the cycloalkylunsubstituted or substituted with 1 or 2 of R^(g) and R^(h) whereinR^(g) and R^(h) are independently selected from alkyl, hydroxy, alkoxy,halo, haloalkyl, and haloalkoxy, more preferably R⁴ is—NH—CH₂-cyclopropyl, —NH—*CH(CH₃)cyclopropyl (where *C is (R) or (S)),—NH—CH₂-cyclobutyl, —NH—*CH(CH₃)cyclobutyl where *C is (R) or (S),—NH—CH₂-cyclopentyl, —NH—CH₂-cyclohexyl, —NH—CH₂-(3-fluorocyclobutyl),—NH—CH₂-(3,3-difluorocyclobutyl), —NH—CH₂-(3,3-dimethylcyclobutyl),—NH—CH₂-(1-methylcyclopropyl), —NH—CH₂-(1-methylcyclobutyl),—NH—(CH₂)₂-cyclopropyl, —NH—(CH₂)₂-cyclopentyl, or NH—(CH₂)₂-cyclohexyl,even more preferably —NH—CH₂-cyclopropyl or NH—CH₂-cyclobutyl. Withinembodiment 14, in another group of compounds, or a pharmaceuticallyacceptable salt thereof, R⁴ is —NH-(hydroxyalkyl) or —NH-(alkoxyalkyl),preferably R⁴ is —NH-(2-hydroxyethyl), —NH-(2-hydroxybutyl),—NH-(2-hydroxy-2-methylbutyl), —NH-(2-hydroxy-2-methylpropyl),—NH-(2-methoxyethyl), —NH-(2-methoxypropyl),—NH-(2-methoxy-2-methylpropyl), or —NH-(2-methoxybutyl). Withinembodiment 14, in another group of compounds, or a pharmaceuticallyacceptable salt thereof, R⁴ is —NH-heterocyclylalkyl, wherein theheterocyclyl of the heterocyclylalkyl is unsubstituted or substitutedwith 1, 2, or 3 of R^(g), R^(h), and R^(i) wherein R^(g), R^(h), andR^(i) are independently selected from alkyl, hydroxy, alkoxy, halo,haloalkyl, and haloalkoxy, preferably R⁴ is —NH—CH₂-oxetan-3-yl,—NH—CH₂-piperidin-4-yl, —NH—CH₂-tetrahydropyran-4-yl,—NH—CH₂-tetrahydrofuran-3-yl, —NH—CH₂-(1-alkylpiperidin-4-yl),—NH—(CH₂)₂-oxetan-3-yl, —NH—(CH₂)₂-piperidin-4-yl,—NH—(CH₂)₂-tetrahydropyran-4-yl, —NH—(CH₂)₂-tetrahydrofuran-3-yl, or—NH—(CH₂)₂-(1-alkylpiperidin-4-yl). Within embodiment 14, in anothergroup of compounds, or a pharmaceutically acceptable salt thereof, R⁴ is—NH-haloalkyl, preferably R⁴ is —NH-2-fluoroethyl,—NH-2,2-difluoroethyl, —NH-(2,2,2-trifluoroethyl), —NH-(3-fluoropropyl),—NH-(3,3-difluoropropyl), or —NH-(3,3,3-trifluoropropyl). Withinembodiment 14, in another group of compounds, or a pharmaceuticallyacceptable salt thereof, R⁴ is —NH-heteroaralkyl unsubstituted orsubstituted with 1 or 2 of R^(g) and R^(h) wherein R^(g) and R^(h) areindependently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, andhaloalkoxy. Within embodiment 14, in another group of compounds, or apharmaceutically acceptable salt thereof, R⁴ is —NH-aralkylunsubstituted or substituted with 1 or 2 of R^(g) and R^(h) whereinR^(g) and R^(h) are independently selected from alkyl, hydroxy, alkoxy,halo, haloalkyl, and haloalkoxy, preferably R⁴ is —NH-(2-phenethyl),—NH-benzyl, or —NH-(2,4-dimethoxybenzyl). Within embodiment 14, inanother group of compounds, or a pharmaceutically acceptable saltthereof, R⁴ is —NH-methyl, —NH-ethyl, —NH-n-propyl, —NH-isopropyl,—N(methyl)(isopropyl), —NH-n-butyl, —NH-isobutyl, —NH-tert-butyl,NH-pentyl (all isomers), —NH-cyclopropyl, —NH-cyclobutyl,—NH(3-hydroxycyclobutyl), —NH-cyclopentyl, —N(methyl)(cyclopentyl),—NH-cyclohexyl, —NH-(3-fluorocyclobutyl), —NH-(3,3-difluorocyclobutyl),—NH-(3,3-dimethylcyclobutyl), —NH-piperidin-4-yl,—NH-tetrahydropyran-4-yl, —NH-oxetan-3-yl, —NH-tetrahydrofuran-3-yl,—NH-(2,6-dimethyltetrahydropyran-4-yl), —NH-(1-alkylpiperidin-4-yl),—NH—CH₂-cyclopropyl, —NH—CH₂-cyclobutyl, —NH—CH₂-cyclopentyl,—NH—CH₂-cyclohexyl, —NH—CH₂-(3-fluorocyclobutyl),—NH—CH₂-(3,3-difluorocyclobutyl), —NH—CH₂-(3,3-dimethylcyclobutyl),—NH—CH₂-(1-methylcyclopropyl), —NH—CH₂-(1-methylcyclobutyl),—NH—(CH₂)₂-cyclopropyl, —NH—(CH₂)₂-cyclopentyl, NH—(CH₂)₂-cyclohexyl,—NH-(2-hydroxyethyl), —NH-(2-hydroxybutyl),—NH-(2-hydroxy-2-methylbutyl), —NH-(2-methoxyethyl),—NH-(2-methoxy-2-methylbutyl), —NH-(2-methoxybutyl), —NH-2-fluoroethyl,—NH-2,2-difluoroethyl, —NH-(2,2,2-trifluoroethyl), —NH-(3-fluoropropyl),—NH-(3,3-difluoropropyl), —NH-(3,3,3-trifluoropropyl), —NH(2-phenethyl),—NH(2-phenethyl), pyrrolidin-1-yl, cyclopropyl, cyclobutyl, orcyclopentyl.15. In embodiment 15, the compounds of any one of embodiments 1 to 10and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein R⁴ is heteroaryl optionally substituted withone or two substituents independently selected from alkyl, halo,hydroxy, and alkoxy. Within embodiment 15, in one group of compounds, ora pharmaceutically acceptable salt thereof, R⁴ is furanyl, pyridyl,pyrrolyl, or pyrimidinyl optionally substituted with one or twosubstituents independently selected from alkyl, halo, hydroxy, andalkoxy. Within embodiment 15, in another group of compounds, or apharmaceutically acceptable salt thereof, R⁴ is 3-pyridyl,5-methylfuran-2-yl, or 5-methylfuran-3-yl.16. In embodiment 16, the compounds of any one of embodiments 1 to 10and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein R⁴ is phenyl optionally substituted with oneor two substituents independently selected from alkyl, halo, hydroxy,and alkoxy.17. In embodiment 17, the compounds of any one of embodiments 1 to 10and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein R⁴ is heterocyclyl optionally substitutedwith 1 or 2 of R^(g) or R^(h) wherein R^(g) and R^(h) are independentlyselected from alkyl, hydroxy, alkoxy, halo, haloalkyl, and haloalkoxy,preferably R⁴ is pyrrolidin-1-yl, tetrahydrofuranyl, ortetrahydropyranyl. Within embodiment 17, in another group of compounds,or a pharmaceutically acceptable salt thereof, R⁴ istetrahydrofuran-2-yl, tetrahydrofuran-3-yl, and tetrahydropyran-4-yl.18. In embodiment 18, the compounds of any one of embodiments 1 to 10and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein R⁴ is cycloalkyl optionally substituted with1 or 2 of R^(g) and R^(h) wherein R^(g) and R^(h) are independentlyselected from alkyl, hydroxy, alkoxy, halo, haloalkyl, and haloalkoxy,preferably R⁴ is cyclopropyl, cyclobutyl, cyclopentyl,3-fluorocyclopentyl, 3,3-difluorocyclopentyl, cyclohexyl, or4-fluorocyclohexyl.19. In embodiment 19, the compounds of any one of embodiments 1 to 10and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein R⁴ is cycloalkenyl, preferably R⁴ iscyclopropenyl, cyclobutenyl, cyclopentenyl, 3-fluorocyclopentyl,3,3-difluorocyclopentenyl, cyclohexenyl, or 4-fluorocyclohexenyl.20. In embodiment 20, the compounds of any one of embodiments 1 to 19and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein R³ is hydrogen, chloro, or —NH-isopropyl.21. In embodiment 21, the compounds of any one of embodiments 1 to 20and groups contained therein, or a pharmaceutically acceptable saltthereof, are those wherein X is carbon or nitrogen. Within embodiment21, in a group of compounds, or a pharmaceutically acceptable saltthereof, wherein X is carbon. Within embodiment 21, in a group ofcompounds, or a pharmaceutically acceptable salt thereof, wherein X isnitrogen.22. In some embodiments, the compounds of embodiment 1, or apharmaceutically acceptable salt thereof, has the structure of Formula(Ia), or a pharmaceutically acceptable salt thereof:

wherein: n is 1, 2, or 3; and R¹, R², R³ and R⁴ are as defined herein,for example, in embodiment 1. Within embodiment 22, alk is —O—(CH₂)₂₋₄,preferably —OCH₂CH₂CH₂—*, wherein * indicates the point of attachment toR¹. Within embodiment 22, R¹ is heterocyclyl, preferably a saturated,5-membered nitrogen-containing heterocyclyl (for example, pyrrolidine).Within embodiment 22, R² is an unsubstituted C₁₋₄ alkoxy, preferablymethoxy. Within embodiment 22, R³ is H. Within embodiment 22, R⁴ isalkyl, cycloalkyl, aryl, heteroaryl, OR^(d), or NR^(e)R^(f) as definedabove. Within embodiment 22, Formula (Ia), or a pharmaceuticallyacceptable salt thereof, has the structure of Formula (Ic), or apharmaceutically acceptable salt thereof:

Within embodiment 22 and Formula (Ic), or a pharmaceutically acceptablesalt thereof, alk is —O—(CH₂)₂₋₄, preferably —OCH₂CH₂CH₂—*, wherein *indicates the point of attachment to R¹; R¹ is heterocyclyl, preferablya saturated, 5-membered nitrogen-containing heterocyclyl (for example,pyrrolidine); R² is an unsubstituted C₁₋₄ alkoxy, preferably methoxy; R³is H; and R⁴ is alkyl, cycloalkyl, aryl, heteroaryl, OR^(d), orNR^(e)R^(f) as defined above.23. In some embodiments, the compounds of embodiment 1, or apharmaceutically acceptable salt thereof, have the structure of Formula(Ib), or a pharmaceutically acceptable salt thereof:

Where R¹, R², R³, R^(e), R^(f) and ring B are as defined herein, forexample, in embodiment 1. Within embodiment 23, alk is —O—(CH₂)₂₋₄,preferably —OCH₂CH₂CH₂—*, wherein * indicates the point of attachment toR¹. Within embodiment 23, R¹ is heterocyclyl, preferably a saturated,5-membered nitrogen-containing heterocyclyl (for example, pyrrolidinyl).Within embodiment 23, R² is an unsubstituted C₁₋₄ alkoxy, preferablymethoxy. Within embodiment 23, R³ is H. Within embodiment 23, ring B isa 5-, 6-, or 7-membered nitrogen containing heterocyclyl that isoptionally substituted. Within embodiment 23, ring B is a 5-, 6-, or7-membered nitrogen containing heterocyclyl substituted with 1 to 4substituents independently selected from C₁₋₄ alkyl, preferably methyl.Within embodiment 23, Formula (Ia), or a pharmaceutically acceptablesalt thereof, has the structure of Formula (Id), or a pharmaceuticallyacceptable salt thereof:

Within embodiment 23 and Formula (Id), or a pharmaceutically acceptablesalt thereof, alk is —O—(CH₂)₂₋₄, preferably —OCH₂CH₂CH₂—*, wherein *indicates the point of attachment to R¹; R¹ is heterocyclyl, preferablya saturated, 5-membered nitrogen-containing heterocyclyl (for example,pyrrolidine); R² is an unsubstituted C₁₋₄ alkoxy, preferably methoxy; R³is H; and ring B is a 5, 6 or 7 membered nitrogen containingheterocyclyl that is optionally substituted. Within embodiment 23 andFormula (Id), or a pharmaceutically acceptable salt thereof, R^(e) is Hor methyl, preferably H. Within embodiment 23 and Formula (Id), or apharmaceutically acceptable salt thereof, R^(f) is H, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, orheterocyclyl, wherein the cycloalkyl, the cycloalkylalkyl, the arakyl,and the heterocyclyl are unsubstituted or substituted with one or two ofmethyl or hydroxy. Preferably, R^(f) is methyl, ethyl, n-propyl,isopropyl, cyclopropyl, cyclopentyl, and cyclohexyl.24. In embodiment 24, the compounds of Formula (I), or apharmaceutically acceptable salt thereof, are those where: Z¹ and Z² areindependently C (when R² or R³ is attached thereto), CH, or N; alk isalkylene wherein one or two carbon atoms of the alkylene chain areoptionally replaced by NR, O, S, or SO₂ (where R is hydrogen or alkyl),and the alkylene chain is optionally substituted with one or twosubstituents independently selected from halo, haloalkyl, haloalkoxy,hydroxyl, and alkoxy, and wherein -alk-R¹ is attached to carbon (a) or(b); R¹ is —NR⁶R⁷ (where R⁶ and R⁷ are independently hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, or haloalkoxyalkyl), unsubstitutedheterocyclyl, heterocyclyl substituted with 1, 2, or 3 of R^(a), R^(b),and R^(c) wherein R^(a), R^(b), and R^(c) are independently selectedfrom alkyl, hydroxyl, alkoxy, halo, haloalkyl, alkylcarbonyl, andhaloalkylcarbonyl), and spiroheterocycloamino wherein a nitrogen atom ofthe spiroheterocycloamino is attached to alk; R² is hydrogen, alkyl,cycloalkyl, halo, hydroxyl, alkoxy, haloalkoxy, or cyano; R³ ishydrogen, alkyl, halo, alkoxy, alkylamino, dialkylamino, or cyano; R⁴ ishydrogen, deuterium, alkyl (optionally substituted with one to ninedeuteriums), cycloalkyl (optionally substituted with one or twosubstituents independently selected from alkyl, hydroxyl, halo, andalkoxy), cycloalkenyl, phenyl (optionally substituted with one or twosubstituents independently selected from alkyl, halo, hydroxyl, andalkoxy), heteroaryl (optionally substituted with one or two substituentsindependently selected from alkyl, halo, hydroxyl, and alkoxy),heterocyclyl (optionally substituted with one or two substituentsindependently selected from alkyl, halo, hydroxyl, and alkoxy), —OR^(d)(where R^(d) is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, halocycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl), or NR^(e)R^(f)(where R^(e) is hydrogen or alkyl and R^(f) is hydrogen, alkyl,deuterated alkyl, acyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,or heterocyclylalkyl), wherein the cycloalkyl, the aryl, the heteroaryl,and the heterocyclyl either alone or as part of the cycloalkylalkyl, thearalkyl, the heteroaralkyl and the heterocyclylalkyl in R^(d) and R^(f)are independently unsubstituted or substituted with 1, 2, or 3 of R^(g),R^(h), and R^(i) wherein R^(g), R^(h), and R^(i) are independentlyselected from alkyl, hydroxyl, alkoxy, halo, haloalkyl, cyano, andhaloalkoxy, and wherein the alkylene of the aralkyl, the heteroaralkyl,the heterocyclylalkyl, and the cycloalkylalkyl in R^(d) and R^(f) isoptionally substituted with one to nine deuteriums; X is carbon ornitrogen; ring B is phenyl, 5- or 6-membered heteroaryl containing onetwo or three heteroatoms independently selected from nitrogen, oxygen,and sulfur, 5- or 6-membered cycloalkyl, spirocycloalkyl, or 5-, 6- or7-membered saturated heterocyclyl, wherein each of the ring(s) of ring Bare unsubstituted or substituted with 1, 2, or 3 of R^(j), R^(k), andR^(l) wherein R^(j), R^(k), and R^(l) independently selected from alkyl,hydroxyl cyano, alkoxy, halo, haloalkyl, and haloalkoxy; or apharmaceutically acceptable salt thereof; provided the compound ofFormula (I) is not: 5-aminobenzo[f][1,7]naphthyridine-8-methanamine or10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridin-5-ol;or a salt thereof.25. In embodiment 25, the compounds of embodiment 1, or apharmaceutically acceptable salt thereof, are those wherein thecompound, or a pharmaceutically acceptable salt thereof, is selectedfrom compound numbers: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103,104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117,118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131,132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145,146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159,160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173,174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187,188, 189, 190, 191, 192, 193, 194 and 195 as shown in Table 1 or Table2, or a parent compound of the salt as shown in Table 1 or Table 2, or apharmaceutically acceptable salt of the parent compound.26. In embodiment 26, the compounds of embodiment 1, or apharmaceutically acceptable salt thereof, are those wherein thecompound, or a pharmaceutically acceptable salt thereof, is selectedfrom compound numbers: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103,104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117,118, 119, 120, 121, 122, 123, 124, 125 and 126, as shown in Table 1, ora parent compound of the salt as shown in Table 1, or a pharmaceuticallyacceptable salt of the parent compound.27. In embodiment 27, the compounds of embodiment 1, or apharmaceutically acceptable salt thereof, are those wherein thecompound, or a pharmaceutically acceptable salt thereof, is selectedfrom compound numbers: 127, 128, 129, 130, 131, 132, 133, 134, 135, 136,137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164,165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178,179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192,193, 194 and 195 as shown in Table 2, or a parent compound of the saltas shown in Table 2, or a pharmaceutically acceptable salt of the parentcompound.28. Embodiment 28 provides a pharmaceutical composition comprising acompound of any one of embodiments 1 to 27, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.29. Embodiment 29 provides a method of inhibiting G9a, comprisingcontacting a cell with a therapeutically effective amount of a compoundof any one embodiments 1 to 27, or a pharmaceutically acceptable saltthereof.30. In embodiment 30, the cell of embodiment 29 can be a cancer cell.31. Embodiment 31, provides a method of ameliorating and/or treating ahemoglobinpathy, comprising administering a therapeutically effectiveamount of a compound of any one of embodiments 1 to 27, or apharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition of embodiment 28 to a subject in need thereof.32. In embodiment 32, the hemoglobinpathy of embodiment 31 can be sicklecell disease or beta-thalassemia.33. Embodiment 33, provides a method of ameliorating and/or treating acancer, comprising administering a therapeutically effective amount of acompound of any one of embodiments 1 to 27, or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition of embodiment28 to a subject in need thereof.34. In embodiment 34, the cancer of embodiment 33 can be selected from:a Colorectal Cancer; a Osteosarcoma Cancer; an Acute LymphoblasticLeukemia (ALL); an Acute Myeloid Leukemia (AML); an AdrenocorticalCarcinoma; a Kaposi Sarcoma (Soft Tissue Sarcoma); an AIDS-RelatedLymphoma (Lymphoma); a Primary CNS Lymphoma; an Anal Cancer; aGastrointestinal Carcinoid Tumor; an Astrocytoma; an AtypicalTeratoid/Rhabdoid Tumor; a Basal Cell Carcinoma of the Skin; a Bile DuctCancer; a Bladder Cancer; a Bone Cancer (includes Ewing Sarcoma andOsteosarcoma and Malignant Fibrous Histiocytoma); a Brain Tumor; aBreast Cancer; a Bronchial Tumor; a Burkitt Lymphoma; a Cardiac Tumor;an Embryonal Tumor (Brain Cancer); a Germ Cell Tumor (Brain Cancer); aPrimary CNS Lymphoma; a Cervical Cancer; a Cholangiocarcinoma; aChordoma; a Chronic Lymphocytic Leukemia (CLL); a Chronic MyelogenousLeukemia (CML); a Chronic Myeloproliferative Neoplasm; aCraniopharyngioma (Brain Cancer); a Cutaneous T-Cell Lymphoma; a DuctalCarcinoma In Situ (DCIS); an Endometrial Cancer (Uterine Cancer); anEpendymoma (Brain Cancer); an Esophageal Cancer; anEsthesioneuroblastoma; an Ewing Sarcoma (Bone Cancer); Extracranial GermCell Tumor; Extragonadal Germ Cell Tumor; Eye Cancer; IntraocularMelanoma; a Retinoblastoma; a Fallopian Tube Cancer; a FibrousHistiocytoma of Bone; a Gallbladder Cancer; a Gastric (Stomach)Gastrointestinal Stromal Tumor (GIST) (Soft Tissue Sarcoma); a CNS GermCell Tumors (Brain Cancer); an Extracranial Germ Cell Tumor; anExtragonadal Germ Cell Tumor; an Ovarian Germ Cell Tumor; a TesticularCancer; a Gestational Trophoblastic Disease; a Hairy Cell Leukemia; aHead and Neck Cancer; a Hepatocellular (Liver) Cancer; a Histiocytosis,a Langerhans Cell; Hodgkin Lymphoma; a Hypopharyngeal Cancer (Head andNeck Cancer); an Intraocular Melanoma; an Islet Cell Tumor; a PancreaticNeuroendocrine Tumor; a Kidney (Renal Cell) Cancer; a Langerhans CellHistiocytosis; a Laryngeal Cancer (Head and Neck Cancer); a Leukemia; aLip and Oral Cavity Cancer (Head and Neck Cancer); a Lung Cancer(Non-Small Cell and Small Cell); a Lymphoma; a Male Breast Cancer; aMelanoma; a Merkel Cell Carcinoma (Skin Cancer); a Mesothelioma; aMalignant Mesothelioma; a Metastatic Squamous Neck Cancer with OccultPrimary (Head and Neck Cancer); a Midline Tract Carcinoma involving NUTGene; a Mouth Cancer (Head and Neck Cancer); Multiple EndocrineNeoplasia Syndromes; Multiple Myeloma/Plasma Cell Neoplasms; a MycosisFungoides (Lymphoma); a Myelodysplastic Syndrome, aMyelodysplastic/Myeloproliferative Neoplasm; a Nasal Cavity andParanasal Sinus Cancer (Head and Neck Cancer); a Nasopharyngeal Cancer(Head and Neck Cancer); a Nasopharyngeal Cancer—Neuroblastoma; aNon-Hodgkin Lymphoma; an Oral Cancer; Lip and Oral Cavity Cancer andOropharyngeal Cancer (Head and Neck Cancer); an Ovarian Cancer; aPancreatic Cancer; a Papillomatosis; a Paraganglioma; a Paranasal Sinusand Nasal Cavity Cancer (Head and Neck Cancer); a Parathyroid Cancer; aPenile Cancer; a Pharyngeal Cancer (Head and Neck Cancer); aPheochromocytoma; a Pituitary Tumor; a Pleuropulmonary Blastoma; aPrimary CNS Lymphoma; a Primary Peritoneal Cancer; a Prostate Cancer; aRectal Cancer; a Rhabdomyosarcoma (Soft Tissue Sarcoma); a SalivaryGland Cancer (Head and Neck Cancer); a Salivary Gland Tumor; a VascularTumor (Soft Tissue Sarcoma); an Uterine Sarcoma; a Sézary Syndrome(Lymphoma); a Small Intestine Cancer; a Squamous Cell Carcinoma; a SkinCancer; a Squamous Neck Cancer with Occult Primary, Metastatic (Head andNeck Cancer); a Cutaneous T-Cell Lymphoma; a Throat Cancer (Head andNeck Cancer); a Nasopharyngeal Cancer; an Oropharyngeal Cancer; aHypopharyngeal Cancer; a Thymoma and Thymic Carcinoma; a Thyroid Cancer;an Urethral Cancer; a Vaginal Cancer; a Vascular Tumor (Soft TissueSarcoma); a Vulvar Cancer; a Myelodysplastic syndrome (MDS); and a WilmsTumor.35. In embodiment 35, the cancer of any one of embodiments 33 to 34 canbe selected from: a Myelodysplastic Syndrome (MDS); an Acute MyeloidLeukemia (AML); an Ovarian Cancer; a Colon Cancer; and a Non-Small CellLung Cancer (NSCLC).36. Embodiment 36, provides a method of ameliorating and/or treating anautoimmune or inflammatory disease in, comprising administering atherapeutically effective amount of a compound of any one of embodiments1 to 27, or a pharmaceutically acceptable salt thereof, or thepharmaceutical composition of embodiment 28 to a subject in needthereof.37. In embodiment 37, the autoimmune or inflammatory disease ofembodiment 36 can be selected from: arthritis, atherosclerosis, multiplesclerosis, myasthenia gravis, Crohn's disease, graft-versus-hostdisease, psoriasis, granulomatous colitis, lymphocyte colitis,collagenous colitis, ulcerative colitis, Coeliac Disease, subepidermalblistering disorders, systemic lupus erythematosus, discoid lupuserythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren'ssyndrome, primary biliary cirrhosis, active chronic hepatitis, chronicfatigue syndrome and vasculitis.38. In embodiment 38, the autoimmune or inflammatory disease of any oneof embodiments 36 to 37 can be Crohn's disease, rheumatoid arthritis,systemic lupus erythematosus, systemic sclerosis, primary biliarycirrhosis and graft-versus-host disease.39. Embodiment 39, provides for the use of an effective amount of acompound of any one embodiments 1 to 27, or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament forinhibiting the activity of G9a in a cell.40. In embodiment 40, the cell of embodiment 39 can be a cancer cell.41. Embodiment 41, provides an effective amount of a compound of any oneembodiments 1 to 27, or a pharmaceutically acceptable salt thereof, forinhibiting the activity of G9a in a cell.42. In embodiment 42, the cell of embodiment 41 can be a cancer cell.43. Embodiment 43, provides for the use of an effective amount of acompound of any one embodiments 1 to 27, or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition of embodiment28, in the manufacture of a medicament for ameliorating and/or treatinga hemoglobinpathy.44. In embodiment 44, the hemoglobinpathy of embodiment 43 can be sicklecell disease or beta-thalassemia.45. Embodiment 45, provides an effective amount of a compound of any oneembodiments 1 to 27, or a pharmaceutically acceptable salt thereof, orthe pharmaceutical composition of embodiment 28, for ameliorating and/ortreating a hemoglobinpathy.46. In embodiment 46, the hemoglobinpathy of embodiment 45 can be sicklecell disease or beta-thalassemia.47. Embodiment 47, provides for the use of an effective amount of acompound of any one embodiments 1 to 27, or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition of embodiment28, in the manufacture of a medicament for ameliorating and/or treatinga cancer.48. In embodiment 48, the cancer of embodiment 47 can be selected from:a Colorectal Cancer; a Osteosarcoma Cancer; an Acute LymphoblasticLeukemia (ALL); an Acute Myeloid Leukemia (AML); an AdrenocorticalCarcinoma; a Kaposi Sarcoma (Soft Tissue Sarcoma); an AIDS-RelatedLymphoma (Lymphoma); a Primary CNS Lymphoma; an Anal Cancer; aGastrointestinal Carcinoid Tumor; an Astrocytoma; an AtypicalTeratoid/Rhabdoid Tumor; a Basal Cell Carcinoma of the Skin; a Bile DuctCancer; a Bladder Cancer; a Bone Cancer (includes Ewing Sarcoma andOsteosarcoma and Malignant Fibrous Histiocytoma); a Brain Tumor; aBreast Cancer; a Bronchial Tumor; a Burkitt Lymphoma; a Cardiac Tumor;an Embryonal Tumor (Brain Cancer); a Germ Cell Tumor (Brain Cancer); aPrimary CNS Lymphoma; a Cervical Cancer; a Cholangiocarcinoma; aChordoma; a Chronic Lymphocytic Leukemia (CLL); a Chronic MyelogenousLeukemia (CML); a Chronic Myeloproliferative Neoplasm; aCraniopharyngioma (Brain Cancer); a Cutaneous T-Cell Lymphoma; a DuctalCarcinoma In Situ (DCIS); an Endometrial Cancer (Uterine Cancer); anEpendymoma (Brain Cancer); an Esophageal Cancer; anEsthesioneuroblastoma; an Ewing Sarcoma (Bone Cancer); Extracranial GermCell Tumor; Extragonadal Germ Cell Tumor; Eye Cancer; IntraocularMelanoma; a Retinoblastoma; a Fallopian Tube Cancer; a FibrousHistiocytoma of Bone; a Gallbladder Cancer; a Gastric (Stomach)Gastrointestinal Stromal Tumor (GIST) (Soft Tissue Sarcoma); a CNS GermCell Tumors (Brain Cancer); an Extracranial Germ Cell Tumor; anExtragonadal Germ Cell Tumor; an Ovarian Germ Cell Tumor; a TesticularCancer; a Gestational Trophoblastic Disease; a Hairy Cell Leukemia; aHead and Neck Cancer; a Hepatocellular (Liver) Cancer; a Histiocytosis,a Langerhans Cell; Hodgkin Lymphoma; a Hypopharyngeal Cancer (Head andNeck Cancer); an Intraocular Melanoma; an Islet Cell Tumor; a PancreaticNeuroendocrine Tumor; a Kidney (Renal Cell) Cancer; a Langerhans CellHistiocytosis; a Laryngeal Cancer (Head and Neck Cancer); a Leukemia; aLip and Oral Cavity Cancer (Head and Neck Cancer); a Lung Cancer(Non-Small Cell and Small Cell); a Lymphoma; a Male Breast Cancer; aMelanoma; a Merkel Cell Carcinoma (Skin Cancer); a Mesothelioma; aMalignant Mesothelioma; a Metastatic Squamous Neck Cancer with OccultPrimary (Head and Neck Cancer); a Midline Tract Carcinoma involving NUTGene; a Mouth Cancer (Head and Neck Cancer); Multiple EndocrineNeoplasia Syndromes; Multiple Myeloma/Plasma Cell Neoplasms; a MycosisFungoides (Lymphoma); a Myelodysplastic Syndrome, aMyelodysplastic/Myeloproliferative Neoplasm; a Nasal Cavity andParanasal Sinus Cancer (Head and Neck Cancer); a Nasopharyngeal Cancer(Head and Neck Cancer); a Nasopharyngeal Cancer—Neuroblastoma; aNon-Hodgkin Lymphoma; an Oral Cancer; Lip and Oral Cavity Cancer andOropharyngeal Cancer (Head and Neck Cancer); an Ovarian Cancer; aPancreatic Cancer; a Papillomatosis; a Paraganglioma; a Paranasal Sinusand Nasal Cavity Cancer (Head and Neck Cancer); a Parathyroid Cancer; aPenile Cancer; a Pharyngeal Cancer (Head and Neck Cancer); aPheochromocytoma; a Pituitary Tumor; a Pleuropulmonary Blastoma; aPrimary CNS Lymphoma; a Primary Peritoneal Cancer; a Prostate Cancer; aRectal Cancer; a Rhabdomyosarcoma (Soft Tissue Sarcoma); a SalivaryGland Cancer (Head and Neck Cancer); a Salivary Gland Tumor; a VascularTumor (Soft Tissue Sarcoma); an Uterine Sarcoma; a Sézary Syndrome(Lymphoma); a Small Intestine Cancer; a Squamous Cell Carcinoma; a SkinCancer; a Squamous Neck Cancer with Occult Primary, Metastatic (Head andNeck Cancer); a Cutaneous T-Cell Lymphoma; a Throat Cancer (Head andNeck Cancer); a Nasopharyngeal Cancer; an Oropharyngeal Cancer; aHypopharyngeal Cancer; a Thymoma and Thymic Carcinoma; a Thyroid Cancer;an Urethral Cancer; a Vaginal Cancer; a Vascular Tumor (Soft TissueSarcoma); a Vulvar Cancer; a Myelodysplastic syndrome (MDS); and a WilmsTumor.49. In embodiment 49, the cancer of any one of embodiments 47 to 48 canbe selected from: a Myelodysplastic Syndrome (MDS); an Acute MyeloidLeukemia (AML); an Ovarian Cancer; a Colon Cancer; and a Non-Small CellLung Cancer (NSCLC).50. Embodiment 50, provides an effective amount of a compound of any oneembodiments 1 to 27, or a pharmaceutically acceptable salt thereof, orthe pharmaceutical composition of embodiment 28, for ameliorating and/ortreating a cancer.51. In embodiment 51, the cancer of embodiment 50 can be selected from:a Colorectal Cancer; a Osteosarcoma Cancer; an Acute LymphoblasticLeukemia (ALL); an Acute Myeloid Leukemia (AML); an AdrenocorticalCarcinoma; a Kaposi Sarcoma (Soft Tissue Sarcoma); an AIDS-RelatedLymphoma (Lymphoma); a Primary CNS Lymphoma; an Anal Cancer; aGastrointestinal Carcinoid Tumor; an Astrocytoma; an AtypicalTeratoid/Rhabdoid Tumor; a Basal Cell Carcinoma of the Skin; a Bile DuctCancer; a Bladder Cancer; a Bone Cancer (includes Ewing Sarcoma andOsteosarcoma and Malignant Fibrous Histiocytoma); a Brain Tumor; aBreast Cancer; a Bronchial Tumor; a Burkitt Lymphoma; a Cardiac Tumor;an Embryonal Tumor (Brain Cancer); a Germ Cell Tumor (Brain Cancer); aPrimary CNS Lymphoma; a Cervical Cancer; a Cholangiocarcinoma; aChordoma; a Chronic Lymphocytic Leukemia (CLL); a Chronic MyelogenousLeukemia (CML); a Chronic Myeloproliferative Neoplasm; aCraniopharyngioma (Brain Cancer); a Cutaneous T-Cell Lymphoma; a DuctalCarcinoma In Situ (DCIS); an Endometrial Cancer (Uterine Cancer); anEpendymoma (Brain Cancer); an Esophageal Cancer; anEsthesioneuroblastoma; an Ewing Sarcoma (Bone Cancer); Extracranial GermCell Tumor; Extragonadal Germ Cell Tumor; Eye Cancer; IntraocularMelanoma; a Retinoblastoma; a Fallopian Tube Cancer; a FibrousHistiocytoma of Bone; a Gallbladder Cancer; a Gastric (Stomach)Gastrointestinal Stromal Tumor (GIST) (Soft Tissue Sarcoma); a CNS GermCell Tumors (Brain Cancer); an Extracranial Germ Cell Tumor; anExtragonadal Germ Cell Tumor; an Ovarian Germ Cell Tumor; a TesticularCancer; a Gestational Trophoblastic Disease; a Hairy Cell Leukemia; aHead and Neck Cancer; a Hepatocellular (Liver) Cancer; a Histiocytosis,a Langerhans Cell; Hodgkin Lymphoma; a Hypopharyngeal Cancer (Head andNeck Cancer); an Intraocular Melanoma; an Islet Cell Tumor; a PancreaticNeuroendocrine Tumor; a Kidney (Renal Cell) Cancer; a Langerhans CellHistiocytosis; a Laryngeal Cancer (Head and Neck Cancer); a Leukemia; aLip and Oral Cavity Cancer (Head and Neck Cancer); a Lung Cancer(Non-Small Cell and Small Cell); a Lymphoma; a Male Breast Cancer; aMelanoma; a Merkel Cell Carcinoma (Skin Cancer); a Mesothelioma; aMalignant Mesothelioma; a Metastatic Squamous Neck Cancer with OccultPrimary (Head and Neck Cancer); a Midline Tract Carcinoma involving NUTGene; a Mouth Cancer (Head and Neck Cancer); Multiple EndocrineNeoplasia Syndromes; Multiple Myeloma/Plasma Cell Neoplasms; a MycosisFungoides (Lymphoma); a Myelodysplastic Syndrome, aMyelodysplastic/Myeloproliferative Neoplasm; a Nasal Cavity andParanasal Sinus Cancer (Head and Neck Cancer); a Nasopharyngeal Cancer(Head and Neck Cancer); a Nasopharyngeal Cancer—Neuroblastoma; aNon-Hodgkin Lymphoma; an Oral Cancer; Lip and Oral Cavity Cancer andOropharyngeal Cancer (Head and Neck Cancer); an Ovarian Cancer; aPancreatic Cancer; a Papillomatosis; a Paraganglioma; a Paranasal Sinusand Nasal Cavity Cancer (Head and Neck Cancer); a Parathyroid Cancer; aPenile Cancer; a Pharyngeal Cancer (Head and Neck Cancer); aPheochromocytoma; a Pituitary Tumor; a Pleuropulmonary Blastoma; aPrimary CNS Lymphoma; a Primary Peritoneal Cancer; a Prostate Cancer; aRectal Cancer; a Rhabdomyosarcoma (Soft Tissue Sarcoma); a SalivaryGland Cancer (Head and Neck Cancer); a Salivary Gland Tumor; a VascularTumor (Soft Tissue Sarcoma); an Uterine Sarcoma; a Sézary Syndrome(Lymphoma); a Small Intestine Cancer; a Squamous Cell Carcinoma; a SkinCancer; a Squamous Neck Cancer with Occult Primary, Metastatic (Head andNeck Cancer); a Cutaneous T-Cell Lymphoma; a Throat Cancer (Head andNeck Cancer); a Nasopharyngeal Cancer; an Oropharyngeal Cancer; aHypopharyngeal Cancer; a Thymoma and Thymic Carcinoma; a Thyroid Cancer;an Urethral Cancer; a Vaginal Cancer; a Vascular Tumor (Soft TissueSarcoma); a Vulvar Cancer; a Myelodysplastic syndrome (MDS); and a WilmsTumor.52. In embodiment 52, the cancer of any one of embodiments 50 to 51 canbe selected from: a Myelodysplastic Syndrome (MDS); an Acute MyeloidLeukemia (AML); an Ovarian Cancer; a Colon Cancer; and a Non-Small CellLung Cancer (NSCLC).53. Embodiment 53, provides for the use of an effective amount of acompound of any one embodiments 1 to 27, or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition of embodiment28, in the manufacture of a medicament for ameliorating and/or treatingan autoimmune or inflammatory disease.54. In embodiment 54, the autoimmune or inflammatory disease ofembodiment 53 can be selected from: arthritis, atherosclerosis, multiplesclerosis, myasthenia gravis, Crohn's disease, graft-versus-hostdisease, psoriasis, granulomatous colitis, lymphocyte colitis,collagenous colitis, ulcerative colitis, Coeliac Disease, subepidermalblistering disorders, systemic lupus erythematosus, discoid lupuserythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren'ssyndrome, primary biliary cirrhosis, active chronic hepatitis, chronicfatigue syndrome and vasculitis.55. In embodiment 55, the autoimmune or inflammatory disease of any oneof embodiments 53 to 54 can be selected from: Crohn's disease,rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis,primary biliary cirrhosis and graft-versus-host disease.56. Embodiment 56, provides an effective amount of a compound of any oneembodiments 1 to 27, or a pharmaceutically acceptable salt thereof, orthe pharmaceutical composition of embodiment 28, for ameliorating and/ortreating an autoimmune or inflammatory disease.57. In embodiment 57, the autoimmune or inflammatory disease ofembodiment 56 can be selected from: arthritis, atherosclerosis, multiplesclerosis, myasthenia gravis, Crohn's disease, graft-versus-hostdisease, psoriasis, granulomatous colitis, lymphocyte colitis,collagenous colitis, ulcerative colitis, Coeliac Disease, subepidermalblistering disorders, systemic lupus erythematosus, discoid lupuserythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren'ssyndrome, primary biliary cirrhosis, active chronic hepatitis, chronicfatigue syndrome and vasculitis.58. In embodiment 58, the autoimmune or inflammatory disease of any oneof embodiments 56 to 57 can be selected from: Crohn's disease,rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis,primary biliary cirrhosis and graft-versus-host disease.

Representative compounds of Formula (I), or salts thereof, are disclosedin Tables 1 and 2 below. Although Tables 1 and 2 may show a specificsalt of a compound of Formula (I), those skilled in the art will be ableto recognize the parent compound (wherein the “parent compound” is acompound without a salt moiety present), and other salts, such aspharmaceutically acceptable salts, of those compounds in Tables 1 and 2.

TABLE 1 MS Cmpd. # Structure Name Found 1

  formate 8-methoxy-N-methyl-7-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 356.2 2

  formate 2-methoxy-N-methyl-3-[3- (pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amine formate 370.2 3

  trifluoroacetate 8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 384.2 4

  trifluoroacetate 2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- cyclopenta[c]quinolin-4- yl}amino)ethan-1-oltrifluoroacetate 386.3 5

  trifluoroacetate 8-methoxy-N-(2-phenylethyl)-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 446.3 6

  formate 8-methoxy-2-methyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4-amine formate 398.4 7

  formate N-cyclobutyl-8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 396.4 8

  trifluoroacetate N-cyclopentyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 410.4 9

  trifluoroacetate 8-methoxy-N-methyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate 398.2 10

  formate 1-{8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}pyrrolidine formate 396.2 11

  trifluoroacetate 8-methoxy-7-[(1-methylpyrrolidin-3-yl)methoxy]-N-(propan-2-yl)- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 370.4 12

  trifluoroacetate 2-methoxy-N-(oxan-4-yl)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10- tetrahydrophenanthridin-6-aminetrifluoroacetate 440.3 13

  formate 2-methoxy-N-(propan-2-yl)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10- tetrahydrophenanthridin-6-amineformate 398.3 14

  trifluoroacetate N-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- cyclopenta[c]quinolin-4- yl}acetamidetrifluoroacetate 384.2 15

  formate 2-({2-methoxy-3-[3-(pyrrolidin-1- yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6- yl}amino)ethan-1-ol formate 400.2 16

  trifluoroacetate (1r,3r)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclobutan-1-ol trifluoroacetate 412.3 17

  formate 8-methoxy-N-[(3R)-oxolan-3-yl]-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- amineformate 412.4 18

  formate 8-methoxy-N-[(3S)-oxolan-3-yl]-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- amineformate 412.4 19

  formate N-cyclopropyl-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10- tetrahydrophenanthridin-6-amineformate 396.2 20

  formate 2-methoxy-6-(methylamino)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10- tetrahydrophenanthridin-8-ol formate386.2 21

  trifluoroacetate 1-[3-({8-methoxy-1H,2H,3H- cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine trifluoroacetate 327.3 22

  trifluoroacetate 8-methoxy-N-methyl-7-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin- 4-amine trifluoroacetate 357.2 23

  trifluoroacetate 8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-pyrrolo[3,2-c]quinolin- 4-aminetrifluoroacetate 385.2 24

  trifluoroacetate 8-methoxy-N,2,2-trimethyl-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-pyrrolo[3,2-c]quinolin- 4-aminetrifluoroacetate 385.2 25

  trifluoroacetate 8-methoxy-2,2-dimethyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1- yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin-4-amine trifluoroacetate 413.2 26

  formate 9-methoxy-N-methyl-8-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[h]1,6- naphthyridin-5-amine formate 371.1 27

  trifluoroacetate 9-methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H,4H-benzo[h]1,6- naphthyridin-5-aminetrifluoroacetate 399.2 28

  trifluoroacetate 1-[3-({9-methoxy-5-methyl- 1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8- yl}oxy)propyl]pyrrolidine trifluoroacetate 356.2 29

  formate 9-methoxy-N,2-dimethyl-8-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[h]1,6- naphthyridin-5-amine formate 385.3 30

  formate 9-methoxy-2-methyl-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H,4H-benzo[h]1,6-naphthyridin-5-amine formate 413.3 31

  trifluoroacetate 1-[3-({9-methoxy-2,5-dimethyl-1H,2H,3H,4H-benzo[h]1,6- naphthyridin-8- yl}oxy)propyl]pyrrolidinetrifluoroacetate 370.2 32

  trifluoroacetate 1-[3-({5-cyclopropyl-9-methoxy-2-methyl-1H,2H,3H,4H-benzo[h]1,6- naphthyridin-8-yl}oxy)propyl]pyrrolidine trifluoroacetate 396.2 33

  formate 10-methoxy-N-methyl-9-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H,5H-azepino[3,2- c]quinolin-6-amine formate 385.2 34

  formate 10-methoxy-N-(propan-2-yl)-9-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H,5H-azepino[3,2- c]quinolin-6-amine formate 413.3 35

  formate 1-[3-({8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin- 7-yl}oxy)propyl]pyrrolidine formate356.2 36

  formate 1-[3-({4-cyclopropyl-8-methoxy- 2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7- yl}oxy)propyl]pyrrolidine formate 396.3 37

  trifluoroacetate 8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-ol trifluoroacetate 343.2 38

  trifluoroacetate 2-methoxy-3-[3-(pyrrolidin-1- yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-ol trifluoroacetate 357.2 39

  trifluoroacetate 2-methoxy-N-[1-(propan-2-yl)piperidin-4-yl]-3-[3-(pyrrolidin- 1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amine trifluoroacetate 481.4 40

  trifluoroacetate 2-methoxy-3-[3-(pyrrolidin-1- yl)propoxy]-7,8,9,10-tetrahydrophenanthridine trifluoroacetate 341.3 41

  formate 2-methoxy-N-(1-methylpiperidin-4-yl)-3-[3-(pyrrolidin-1-yl)propoxy]- 7,8,9,10-tetrahydrophenanthridin-6-amine formate 439.4 42

  formate 2-methoxy-N-(oxan-4-yl)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10- tetrahydrophenanthridin-6-amineformate 425.3 43

  formate N-{8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}-1- (propan-2-yl)piperidin-4-amine formate467.4 44

  formate 8-methoxy-N-(oxetan-3-yl)-7-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 398.3 45

7-methoxy-N-(propan-2-yl)-8-[3- (pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine 386.3 46

8-methoxy-N-(propan-2-yl)-7-[3- (pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine 386.4 47

N-cyclopropyl-7-methoxy-8-[3- (pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine 384.3 48

N-cyclopropyl-8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine 384.3 49

  formate N-(cyclobutylmethyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- amineformate 410.3 50

  formate 9-methoxy-N-(propan-2-yl)-8-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]quinolin-5- amine formate 400.3 51

  formate 2-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]-N-(propan-2-yl)- 7,8,9,10-tetrahydrophenanthridin-6- amineformate 384.3 52

  formate 9-methoxy-N-(propan-2-yl)-8-[3- (pyrrolidin-1-yl)propoxy]benzo[h]1,6- naphthyridin-5-amine formate 395.4 53

  formate 8-methoxy-N,2,2-trimethyl-7-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 384.3 54

  formate 8-methoxy-2,2-dimethyl-N- (propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- cyclopenta[c]quinolin-4-amine formate 412.3 55

  formate N-cyclopropyl-9-methoxy-8-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]quinolin-5- amine formate 398.2 56

  formate 9-methoxy-8-[3-(pyrrolidin-1- yl)propoxy]pyrazolo[1,5-c]quinazolin-5-ol formate 57

  formate 9-methoxy-N-methyl-8-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]quinolin-5- amine formate 372.2 58

  formate N-ethyl-9-methoxy-8-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]quinolin-5- amine formate 386.2 59

  formate 8-methoxy-N-methyl-7-[3- (pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine formate 358.2 60

  formate N-ethyl-8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine formate 372.2 61

  formate 2-methoxy-6-(methylamino)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10- tetrahydrophenanthridin-8-ol formate386.2 62

  formate 1-({8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}amino)cyclopropane-1- carboxylic acidformate 426.2 63

  formate 6-fluoro-8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4-amine formate 402.2 64

  formate 3-({2-methoxy-3-[3-(pyrrolidin-1- yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6- yl}amino)cyclobutan-1-ol formate 426.3 65

  formate 8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-N-(2,2,2-trifluoroethyl)-1H,2H,3H- cyclopenta[c]quinolin-4-amine formate 424.3 66

8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-N-(3,3,3-trifluoropropyl)-1H,2H,3H- cyclopenta[c]quinolin-4-amine 438.4 67

  formate 2-methoxy-3-[3-(pyrrolidin-1- yl)propoxy]-N-(2,2,2-trifluoroethyl)-7,8,9,10- tetrahydrophenanthridin-6-amine formate 438.468

  trifluoroacetate 2-methoxy-6-[(propan-2-yl)amino]-3-[3-(pyrrolidin-1-yl)propoxy]- 7,8,9,10-tetrahydrophenanthridin-8- oltrifluoroacetate 414.2 69

  trifluoroacetate 8-methoxy-N-methyl-N-phenyl-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 432.2 70

  formate 1-{8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}pyrrolidine formate 396.2 71

  formate 9-methoxy-3-methyl-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H,4H-benzo[c]2,7-naphthyridin-5-amine formate 413.3 72

  trifluoroacetate 8-methoxy-N-methyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4-amine trifluoroacetate 398.3 73

  trifluoroacetate N-cyclopentyl-8-methoxy-N- methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- cyclopenta[c]quinolin-4-amine trifluoroacetate424.3 74

  formate N-ethyl-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- amineformate 398.3 75

  Formate 3-({9-methoxy-2,2-dimethyl- 1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8- yl}oxy)propyl]pyrrolidine formate 370.2 76

  Formate 1-[3-({5-cyclopropyl-9-methoxy- 2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8- yl)oxy)propyl]pyrrolidine formate 410.5 77

  Formate 1-(3-{[9-methoxy-2,2-dimethyl-5- (propan-2-yl)-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8- yl]oxy}propyl)pyrrolidine formate 412.5 78

  Formate 1-[3-({9-methoxy-2,2,5-trimethyl- 1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8- yl}oxy)propyl]pyrrolidine formate 384.4 79

  Trifluroracetate 1-[3-({6-cyclopentyl-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2- c]quinolin-9- yl}oxy)propyl]pyrrolidinetrifluoroacetate 424.3 80

  trifluoroacetate 1-[3-({6-cyclopropyl-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2- c]quinolin-9- yl}oxy)propyl]pyrrolidinetrifluoroacetate 396.3 81

  trifluoroacetate 1-(3-{[10-methoxy-6-(propan-2-yl)-1H,2H,3H,4H,5H-azepino[3,2- c]quinolin-9- yl]oxy}propyl)pyrrolidinetrifluoroacetate 398.2 82

  trifluoroacetate 1-[3-({10-methoxy-6-methyl-1H,2H,3H,4H,5H-azepino[3,2- c]quinolin-9- yl}oxy)propyl]pyrrolidinetrifluoroacetate 370.2 83

  Formate 1-(3-{[4-(cyclopent-1-en-1-yl)-8-methoxy-2,2-dimethyl-1H,2H,3H- pyrrolo[3,2-c]quinolin-7-yl]oxy}propyl)pyrrolidine formate 422.1 84

  trifluoroacetate 4-[(propan-2-yl)amino]-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-8- oltrifluoroacetate 370.3 85

  Formate 8-methoxy-7-[3-(piperidin-1- yl)propoxy]-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 398.3 86

  Formate 7-[3-(3,3-dimethylpyrrolidin-1-yl)propoxy]-8-methoxy-N-(propan- 2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate 412.3 87

  Formate 8-methoxy-2,2-dimethyl-N-(3- methylbutyl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- cyclopenta[c]quinolin-4-amine formate 440.1 88

  Formate N-[(1S)-1-cyclopropylethyl]-8- methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- cyclopenta[c]quinolin-4-amine formate 410.2 89

  Formate N-[(1R)-1-cyclopropylethyl]-8- methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- cyclopenta[c]quinolin-4-amine formate 410.2 90

  Formate 1-(3-{[8-methoxy-4-(5- methylfuran-3-yl)-1H,2H,3H-cyclopenta[c]quinolin-7- yl]oxy}propyl)pyrrolidine formate 407.2 91

  Formate N-butyl-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- amineformate 426.1 92

  Formate 7-[3-(dimethylamino)propoxy]-8- methoxy-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 358.2 93

  Formate 7-[3-(diethylamino)propoxy]-8- methoxy-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 386.3 94

  Formate N-tert-butyl-8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 398.2 95

  Formate N-isobutyl-8-methoxy-2,2- dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H- cyclopenta[c]quinolin-4-amine formate 426.196

  Formate N-(cyclobutylmethyl)-8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1- yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine formate 438.1 97

  Formate N-(cyclopropylmethyl)-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1- yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate 424.1 98

  Formate 1-(3-{[8-methoxy-4-(oxolan-3-yl)-1H,2H,3H-cyclopenta[c]quinolin-7- yl]oxy}propyl)pyrrolidine formate397.2 99

  Formate N-[(2S)-butan-2-yl]-8-methoxy-7- [3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 398.4 100

  Formate N-[(2R)-butan-2-yl]-8-methoxy-7- [3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 398.4 101

  Formate N-(2,2-dimethylpropyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- amineformate 412.3 102

8-methoxy-N-[(2-²H)propan-2-yl]- 7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- amine hydrochloride 385.2 103

  trifluoroacetate 8-methoxy-N-(2-methylpropyl)-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 398.2 104

  Trifluoroacetic acid 8-methoxy-N-propyl-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 384.2 105

  Trifluoroacetic acid N-cyclopropyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 382.2 106

  Trifluoroacetic acid N-ethyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 370.2 107

  Trifluoroacetic acid N-cyclohexyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 424.4 108

  Trifluoroacetic acid N-(cyclopropylmethyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 396.4 109

  Formate 1-[3-({4-cyclopentyl-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7- yl}oxy)propyl]pyrrolidine formate395.2 110

  trifluoroacetate 1-[3-({4-cyclohexyl-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7- yl}oxy)propyl]pyrrolidinetrifluoroacetate 409.3 111

  Formate 1-[3-({8-methoxy-4-phenyl- 1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine formate 403.1 112

  Trifluoroacetate 8-methoxy-7-[3-(morpholin-4-yl)propoxy]-N-(propan-2-yl)- 1H,2H,3H-cyclopenta[c]quinolin-4- aminetrifluoroacetate 400.2 113

  2 HCl 1-[3-({4-cyclopentyl-8-methoxy- 2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7- yl}oxy)propyl]pyrrolidine hydrochloride 424.1114

  Formate 1-[3-({8-methoxy-2,2-dimethyl-4- phenyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7- yl}oxy)propyl]pyrrolidine formate 432.1 115

  Formate N-[(2,4-dimethoxyphenyl)methyl]- 8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- cyclopenta[c]quinolin-4-amine formate 492.1 116

  Formate 8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine formate 342.1 117

  Formate N-[(2,4-dimethoxyphenyl)methyl]- 8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- amineformate 520.1 118

  Formate 8-methoxy-2,2-dimethyl-7-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- amine formate 370.1 119

  Formate 3-({8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}amino)propanenitrile formate 395.2 120

  Formate 8-methoxy-N-[2- (methylsulfanyl)ethyl]-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4- amineformate 416.2 121

  (1:1 mixture as formate salt) and (1S,3R)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-ol formate and (1R,3S)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-ol (1:1 mixture) formate and 440.2

  (1:1 mixture as formate salt) (1S,3R)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-ol formate and (1R,3S)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-ol (1:1 mixture) formate 122

  Formate (1S,2S)-2-({8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}amino)cyclohexan-1-ol formate 440.2123

  Formate (1R,4R)-4-({8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}amino)cyclohexan-1-ol formate 440.2124

  Formate (1S,2S)-2-({8-methoxy-7-[3- (pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}amino)cyclopentan-1-ol formate426.1 125

  1:1 mixture in formate salt form (1R,2S)-2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]- 1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclopentan-1-ol formate 426.1 126

  Formate 3-({8-methoxy-7-[3-(pyrrolidin-1- yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}amino)cyclopentan-1-ol formate 426.1

TABLE 2 Cmpd # Structure Name 127

8-methoxy-4-(5-methylfuran-2-yl)-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinoline 128

8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(tetrahydrofuran-3-yl)-2,3-dihydro-1H- cyclopenta[c]quinoline 129

4-(3-fluorocyclopentyl)-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinoline 130

4-(3,3-difluorocyclopentyl)-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinoline 131

8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-cyclopenta[c]quinoline 132

4-(4-fluorocyclohexyl)-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinoline 133

8-methoxy-4-(pyridin-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinoline 134

N-ethyl-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrospiro[cyclopenta[c]quinoline-2,1′-cyclopropan]-4- amine 135

N-ethyl-8′-methoxy-7′-(3-(pyrrolidin-1-yl)propoxy)-1′,3′-dihydrospiro[cyclobutane-1,2′-cyclopenta[c]quinolin]-4′- amine 136

N-ethyl-8′-methoxy-7′-(3-(pyrrolidin-1-yl)propoxy)-1′,3′-dihydrospiro[cyclopentane-1,2′-cyclopenta[c]quinolin]-4′- amine 137

N-ethyl-2,2-difluoro-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- amine 138

N-ethyl-8′-methoxy-7′-(3-(pyrrolidin-1-yl)propoxy)-1′,3′-dihydrospiro[cyclohexane-1,2′-cyclopenta[c]quinolin]-4′- amine 139

9-chloro-8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H- cyclopenta[c]quinolin-4-amine 140

8-methoxy-N4,N9-bis(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinoline-4,9- diamine 141

8-methoxy-2,2-dimethyl-4-(5-methylfuran-2-yl)-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-pyrrolo[3,2- c]quinoline 142

8-methoxy-2,2-dimethyl-4-(5-methylfuran-3-yl)-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-pyrrolo[3,2- c]quinoline 143

8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-4-(tetrahydrofuran-2-yl)-2,3-dihydro-1H-pyrrolo[3,2- c]quinoline 144

4-(cyclohex-1-en-1-yl)-8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-pyrrolo[3,2- c]quinoline 145

4-cyclohexyl-8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline 146

4-cyclopentyl-8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline 147

8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-4-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-pyrrolo[3,2- c]quinoline 148

8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-4-(tetrahydrofuran-3-yl)-2,3-dihydro-1H-pyrrolo[3,2- c]quinoline 149

8-methoxy-N-(1-methylcyclopropyl)-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- amine 150

N-cyclohexyl-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine 151

ethyl 1-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}amino)cyclopropane-1-carboxylate152

N-benzyl-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine 153

(S)-N-(1-cyclobutylethyl)-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- amine 154

(R)-N-(1-cyclobutylethyl)-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- amine 155

8-methoxy-N-(2-methoxyethyl)-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- amine 156

8-methoxy-N-(2-methoxypropyl)-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- amine 157

8-methoxy-N-(2-methoxy-2-methylpropyl)-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H- cyclopenta[c]quinolin-4-amine158

1-((8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-yl)amino)-2- methylpropan-2-ol 159

4-((8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- yl)amino)butanenitrile 160

1-((8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- yl)amino)cyclopropane-1-carbonitrile161

2-((8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- yI)amino)cyclopropane-1-carbonitrile162

8-methoxy-N-(propan-2-yl-2-d)-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydto-1H-cyclopenta[c]quinolin-4- amilie 163

(R)-7-(3-(3-fluoropyrrolidin-1-yl)propoxy)-N-isopropyl-8-methoxy-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine 164

(S)-7-(3-(3-fluoropyrrolidin-1-yl)propoxy)-N-isopropyl-8-methoxy-2,3-dihydro-1H-cyclopenta[c]quinoIin-4-amine 165

7-(2-fluoro-3-(pyrrolidin-1-yl)propoxy)-N-isopropyl-8-methoxy-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine 166

N-isopropyl-8-methoxy-7-(2-methyl-3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- amine 167

N-isopropyl-8-methoxy-7-(2-methoxy-3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4- amine 168

N-isopropyl-8-methoxy-7-(3-(pyrrolidin-1-yl)-2-(trifluoromethoxy)propoxy)-2,3-dihydro-1H- cyclopenta[c]quinolin-4-amine169

8-ethoxy-N-isopropyl-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine 170

8-ethoxy-N-ethyl-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine 171

N-isopropyl-8-methoxy-1,3-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolin-4-amine 172

(1S,3R)-N-isopropyl-8-methoxy-1,3-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolin- 4-amine 173

(1R,3R)-N-isopropyl-8-methoxy-1,3-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolin- 4-amine 174

(1R,3S)-N-isopropyl-8-methoxy-1,3-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolin- 4-amine 175

(1S,3S)-N-isopropyl-8-methoxy-1,3-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolin- 4-amine 176

N-isopropyl-8-methoxy-3,3-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolin-4-amine 177

N-isopropyl-8-methoxy-1,1-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolin-4-amine 178

N-isopropyl-8-methoxy-1,1,3,3-tetramethyl-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolin- 4-amine 179

N-ethyl-8-methoxy-1,1,3,3-tetramethyl-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolin-4-amine 180

8-methoxy-N,1,1,3,3-pentamethyl-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolin-4-amine 181

N-ethyl-9-methoxy-3-methyl-8-(3-(pyrrolidin-1-yl)propoxy)-3,4-dihydro-1H-pyrano[4,3-c]quinolin-5- amine 182

N-ethyl-9-methoxy-3,3-dimethyl-8-(3-(pyrrolidin-1-yl)propoxy)-3,4-dihydro-1H-pyrano[4,3-c]quinolin-5- amine 183

N-ethyl-9-methoxy-1,3-dimethyl-8-(3-(pyrrolidin-1-yl)propoxy)-3,4-dihydro-1H-pyrano[4,3-c]quinolin-5- amine 184

9-methoxy-N,1,3-trimethyl-8-(3-(pyrrolidin-1-yl)propoxy)-3,4-dihydro-1H-pyrano[4,3-c]quinolin-5- amine 185

9-methoxy-N,3,3-trimethyl-8-(3-(pyrrolidin-1-yl)propoxy)-3,4-dihydro-1H-pyrano[4,3-c]quinolin-5- amine 186

N-ethyl-9-methoxy-2,4-dimethyl-8-(3-(pyrrolidin-1-yl)propoxy)-1,4-dihydro-2H-pyrano[3,4-c]quinolin-5- amine 187

N-ethyl-9-methoxy-2,2-dimethyl-8-(3-(pyrrolidin-1-yl)propoxy)-1,4-dihydro-2H-pyrano[3,4-c]quinolin-5- amine 188

2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)acetic acid 189

ethyl 2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)acetate 190

2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}amino)propanoic acid 191

ethyl 2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4- yl}amino)propanoate 192

2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)-3- methylbutanoic acid 193

ethyl 2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)-3- methylbutanoate 194

2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)-2- methylpropanoic acid 195

ethyl 2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)-2- methylpropanoate

General Synthetic Scheme

Compounds of this disclosure can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Sigma-AldrichChemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or areprepared by methods known to those skilled in the art followingprocedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and Supplementals (ElsevierScience Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wileyand Sons, 1991), March's Advanced Organic Chemistry, (John Wiley andSons, 4th Edition) and Larock's Comprehensive Organic Transformations(VCH Publishers Inc., 1989). These schemes are merely illustrative ofsome methods by which the compounds of this disclosure can besynthesized, and various modifications to these schemes can be made andwill be suggested to one skilled in the art reading this disclosure. Thestarting materials, the intermediates, and the final products of thereaction(s) may be isolated and purified if desired using conventionaltechniques, including but not limited to filtration, distillation,crystallization, chromatography and the like. Such materials may becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., such as from about 0° C. to about 125° C. andfurther such as at about room (or ambient) temperature, e.g., about 20°C. The routes shown and described herein are illustrative only and arenot intended, nor are they to be construed, to limit the scope of theclaims in any manner whatsoever. Those skilled in the art will be ableto recognize modifications of the disclosed syntheses and to devisealternate routes based on the disclosures herein; all such modificationsand alternate routes are within the scope of the claims.

Compounds of Formula (I) where ring B is cycloalkyl or 5-, 6-, or7-membered saturated heterocyclyl, Z¹ and Z² are independently selectedfrom CH or C (wherein a substituent is attached), X is C, and R¹, R²,R³, and R⁴ are as defined in the Summary, can be prepared by thefollowing procedure described in Scheme 1 below.

Reaction of a compound of formula 1 where -alk-R¹, R² and R³ are asdefined in the Summary, or a precursor group thereof with2-oxocycloalkylcarboxylate or 2-oxo heterocyclylcarboxylate of formula 2wherein R is alkyl and ring B is unsubstituted or substituted withR^(j), R^(k), R^(l), and/or R^(m) as defined in the Summary, in thepresence of catalytic amount of an acid, such as p-toluenesulfonic acid,followed by treating the resulting intermediate with poly phosphoricacid at 90° C. to refluxing temperature provides an annular tricycliccompound of Formula (I) where R⁴ is hydroxy. Compounds of formula 1 canbe prepared from commercially available materials such as2-methoxy-5-nitrophenol by methods well known in the art (see referencesin the synthetic examples below). Compounds of formula 2 such as methyl2-oxocyclopentane-1-carboxylate, methyl 2-oxocyclohexane-1-carboxylate,methyl 4-oxotetrahydrofuran-3-carboxylate, and methyl1-methyl-4-oxopiperidine-3-carboxylate are commercially available. Othercompounds of formula 2 are readily available through syntheticprocedures well known to those in the art (e.g., methyl4,4-dimethyl-2-oxocyclopentane-1-carboxylate and the close analogs, seeGellman et al, Organic Letters, 2004, Vol 6, No. 24, page 4411-4414).Compound of Formula (I) where R⁴ is hydroxy can be converted to othercompounds of Formula (I) by first converting it into a correspondingcompound where R⁴ is halo, e.g., chloro, followed by othertransformations. The reaction conditions used for these transformationsdepend on the nature of the R⁴ groups. For example, compounds of Formula(I) where R⁴ is NR^(e)R^(f) (where R^(e) and R^(f) are as defined in theSummary) can be prepared by reacting the corresponding compound where R⁴is halo, such as chloro, with an amine of formula NHR^(e)R^(f) underBuchwald coupling reaction condition. Compounds of Formula (I) where R⁴is alkyl, cycloalkyl, -cycloalkenyl, heterocyclyl, phenyl, orheteroaryl, can be prepared by reacting corresponding compound where R⁴is chloro with either a boronic reagents under Suzuki coupling reactionconditions, Zn reagent under Negishi coupling, or tin derivatives underStille coupling reaction conditions. It will be recognized by a personskilled in the art that, R¹, R², and R³ groups can be modified, asnecessary, during the above synthetic route.

Alternatively, compounds of Formula (I) where Z¹ and Z² areindependently selected from CH or C (wherein a substituent is attached),X is C, and ring B, R¹, R², R³, and R⁴ are as defined in the Summary,can be prepared by the following procedure described in Scheme 2 below.

Compounds of Formula (I) can also be prepared following the syntheticroutes depicted in Scheme 2. Coupling reaction of compound of formula 3where -alk-R¹, R² and R³ are as defined in the Summary or a precursorgroup thereof, with a compound of formula 4 (wherein ring C is phenyl,5- or 6-membered heteroaryl, 5- or 6-membered cycloalkenyl, or 5-, 6-,or 7-membered heterocycloalkenyl each aforementioned ring substitutedwith R^(j), R^(k), R^(l), and/or R^(m) as defined in the Summary, W is—B(OH)₂, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl-, tributylstannyl orother appropriate functional groups and R′ is H or alkyl) in thepresence of appropriate catalysts such as tetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) gives anintermediate compound of formula 5. Compound of formula 3 such as1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine can be madefrom commercially available material, such as 4-bromo-2-methoxyphenol,through methods well known to those skilled in the art (see syntheticexamples below for reference). Compounds of formula 4 can be purchasedfrom commercial resources. Alternatively, compound 4 where W is4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl or 1,1,1-tributylstannane canbe made from compound of formula 7 (where M is halo and R′ is as definedabove) by reacting compound 7 with appropriate reagents such as4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) or1,1,1,2,2,2-hexabutyldistannane in the presence of a suitable catalystsuch as tetrakis(triphenylphosphine) palladium (0) or[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II),respectively. Compound 4 where W is4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl can be subjected to hydrolysisto give corresponding compound of formula 4 where W is —B(OH)₂.Compounds of formula 7 where M is Br or Cl, such as ethyl4-chlorothiazole-5-carboxylate, methyl 2-bromobenzoate, methyl4-chloro-1H-imidazole-5-carboxylate, methyl 2-chloronicotinate, methyl3-chloropyrazine-2-carboxylate, methyl 4-chloropyrimidine-5-carboxylate,ethyl 5-chloro-1H-pyrazole-4-carboxylate, 3-bromothiophene-2-carboxylicacid, or 2-bromo-3-thiophenecarboxylic acid are commercially available.Compound 7 where M is —OTf can be made from the correspondingcommercially available starting material of 2-oxocycloalkylcarboxylateor 2-oxo heterocyclocarboxylate, such as 1-tert-butyl 3-methyl4-oxopiperidine-1,3-dicarboxylate, by methods well known to thoseskilled in the art (see Organic Letters, 2012, 14(12): 2940-2943; andOrganic letters, 2003, 5(1):59-61).

Alternatively, compound of formula 5 can be prepared by reacting anorganoborane compound of formula 6 with a compound of formula 7 undercoupling conditions described above. Compound of Formula (I) is madefrom compound 5 by reduction of the nitro group under suitable reductionconditions such as treatment with Zn, Fe, tin(II) chloride, or underhydrogenation conditions, such as Pd/C under hydrogen atmosphere,followed by hydrolysis of the ester group (where R′=-alkyl) under basicreaction conditions (for example, sodium hydroxide (NaOH) or lithiumhydroxide (LiOH)) to give an amino compound of formula 8. Intramolecularamide coupling reaction of compound 8 facilitated by amide couplingreagents well known to those skilled in the art, such as1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (HATU) and hydroxybenzotriazole (HOBt),1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (EDCI) and HOBt, orbenzotriazol-1-yl-oxytripyrrolidino-phosphonium hexafluorophosphate(PyBOP) in an appropriate solvent, such as dimethylformamide (DMF) or1,4-dioxane, at ambient temperature provides a compound of Formula (I)where R⁴ is hydroxy which can be converted to other compound of Formula(I) as described above in Scheme 1.

Alternatively, compounds of Formula (I) where Z¹ and Z² areindependently selected from CH and C (wherein a substituent isattached), X is C, ring B is saturated heterocyclyl shown in thestructure below and R¹, R², R³, and R⁴ are as defined in the Summary,can be prepared by the following procedure described in Scheme 3.

Reaction of a compound of formula 1 where -alk-R¹, R² and R³ are asdefined in the Summary or a precursor group thereof, with a 5-, 6-, or7-membered heterocycloalkyl compound of formula 9 unsubstituted orsubstituted with R^(j), R^(k), R^(l), and/or R^(m) as defined in theSummary, e.g., pyrrolidine-3-carboxylic acid,2-oxopiperidine-3-carboxylic acid or 2-oxoazepane-3-carboxylic acidwhere PG is a suitable nitrogen protecting group (such as benzyl,p-methoxybenzyl or Boc) in the presence of an amide coupling agent (suchas 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (HATU) and hydroxybenzotriazole (HOBt),1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (EDCI) and HOBt, orbenzotriazol-1-yl-oxytripyrrolidino-phosphonium hexafluorophosphate(PyBOP)) in an appropriate solvent (such as dimethylformamide (DMF) or1,4-dioxane) at ambient temperature gives compound 10.

Compounds of formula 9 can be prepared as shown below:

Compounds of formula 9 can be prepared from a 5-, 6-, or 7-memberedheterocyclyl compound of formula 13 by deprotonation of compound 13 witha suitable base such as ^(t)BuLi or lithium diisopropylamide (LDA)followed by treatment with dry CO₂ gas (see Zhang et. al., OrganicLetters, 2016, 18(3):348-351 for a representative method.). Compounds offormula 13 such as 1-benzyl-2-pyrrolidinone and 1-benzylpiperidin-2-oneare commercially available. Compounds of formula 13 can also be made byprotecting the nitrogen atom of a commercially available lactam offormula 12 (such as azepan-2-one, 2-piperidinone,6-methyl-2-piperidinone, 6,6-dimethylpiperidin-2-one, and5,5-dimethylpyrrolidin-2-one), e.g., by reacting 12 under alkylatingreaction conditions (such as with either benzyl chloride (BnCl) orp-methoxy benzyl chloride (PMBCl) under sodium hydride (NaH) orpotassium carbonate (K₂CO₃) mediated condition) in appropriate solvents,such as tetrahydrofuran (THF) or dimethylformamide (DMF). Compounds offormula 13 where PG is Boc can be made by treating a lactam of formula12 (such as azepan-2-one, 2-pyrrolidinone, 2-piperidinone,6-methyl-2-piperidinone, 6,6-dimethylpiperidin-2-one,5,5-dimethylpyrrolidin-2-one, etc.) with di-tert-butyl dicarbonate inthe presence of 4-dimethylaminopyridine in appropriate solvent(s), suchas acetonitrile or dimethylformamide (DMF).

Alternatively, compounds of formula 9 can be made by hydrolysis of theester group in compounds of formula 14 with a base, such as sodiumhydroxide (NaOH) or lithium hydroxide (LiOH). Compounds of formula 14can be made by deprotonation of compound 12 with bases, such as ^(t)BuLior lithium diisopropylamide (LDA), followed by treatment with dimethylcarbonate.

Treatment of compound 10 with POCl₃ at 90° C. to refluxing temperaturefor up to 16 h provides a compound of Formula 11a where R⁴ is chloro(when PG is Boc or methoxybenzyl) or formula 11b (when PG is benzyl).Removal of the amino protecting group in 11b provides a compound offormula 11a. Compounds of formula 11a can be converted to compounds ofFormula (I) as described herein.

Compounds of Formula (I) where Z¹ is N, Z² is CH or C (wherein asubstituent is attached), X is C, and ring B, R¹, R², R³, and R⁴ are asdefined in the Summary, can be prepared by the following proceduredescribed in Scheme 4 below.

Reaction of a compound of formula 15 where -alk-R¹, R² and R³ are asdefined in the Summary or a precursor group thereof, with a compound offormula 4 under reaction conditions described in Scheme 2 provides acompound of formula 16. Compounds of formula 15 can be made by methodswell known in the art. For example,2-bromo-6-methoxy-3-nitro-5-[3-(pyrrolidin-1-yl)propoxy]pyridine and6-bromo-2-methoxy-5-nitro-N-[3-(pyrrolidin-1-yl)propyl]pyridin-3-aminecan be made from the commercially available 3-hydroxy-pyridine and3-aminopyridine by methods known to those skilled in the art (seeliterature procedures such as Australian Journal of Chemistry, 1981,34(4):927-932; Bioorganic and Medicinal Chemistry Letters, 2014,24(24):5630-5634; WO 2008/101682 A2, and Journal of HeterocyclicChemistry, 1972, 9:1039-1043). Compound 16 can be converted to compoundof Formula (I) where R⁴ is hydroxy as described in Scheme 2 herein andother compound of Formula (I) as described in Scheme 1 herein.

Alternatively, compound 15 can be converted to a compound of Formula (I)following the method illustrated in Methods (i) and (ii) herein.

In Method (i), Compound 15 is first converted to a compound of formula17 where Y is 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl-, —B(OH)₂,-tributylstannyl, or other appropriate functional groups. Compound 17 isthen reacted with a compound of formula 7 as described in Scheme 2herein to give a compound of formula 16, which after nitro groupreduction, ester hydrolysis, and intramolecular amide coupling reactionprovides compound of Formula (I) (where R⁴ is hydroxy) which can beconverted to other compound of Formula (I) as described above in Scheme1.

In Method (ii), compound 15 is converted to a compound of formula 18(where P¹ and P² are independently selected from H and Boc) by reductionof the nitro group with a suitable reducing agent, such as tin(II)chloride, followed by reaction of the resulting amino compound 18 (whereP¹ and P² are each hydrogen) with di-tert-butyl dicarbonate in thepresence of 4-dimethylaminopyridine to give the corresponding compound18 (where P¹ and/or P² is Boc). Compound 18 is reacted with compound 4under conditions similar as described above in Scheme 2 to provide acompound of formula 19 which is then converted to a compound of Formula(I) wherein R⁴ is hydroxy after removal of the amino protecting group(s)and/or intramolecular amide coupling, if needed, as described above.Compound of Formula (I) wherein R⁴ is hydroxy is further transformedinto compound of Formula (I) wherein R⁴ is other appropriate groupsfollowing the procedure similar to those described above.

Compounds of Formula (I) where Z¹ is N, CH or C, Z² is N, X is C, andring B, R¹, R², R³, and R⁴ are as defined in the Summary, can beprepared by the following procedure described in Scheme 5.

Reaction of a compound of formula 20 (wherein -alk-R¹, R² and R³ are asdefined in the Summary or a precursor group thereof, and Z¹ is either N,C or CH), with a compound of formula NHPG¹PG² (where PG¹ and PG² areeither H or a suitable nitrogen protecting group such as benzyl,p-methoxybenzyl or Boc), followed by coupling reaction of the resultingamino compound 21 with compound 4 under reaction conditions describedherein provides a compound of formula 22. Removal of the aminoprotecting groups (for example, with acid such as TFA or HCl when PG¹and/or PG² is -p-methoxybenzyl) provides a compound of formula 23, whichcan be converted to a compound of Formula (I) subsequently by esterhydrolysis (for example, with a base such as NaOH or LiOH, when R′ isalkyl) and intramolecular amide coupling reaction under conditionsdescribed herein if needed. In some cases, the intermediate compound 23(wherein R′ is not H) can cyclize directly into compound of Formula (I).Compounds of formula 20 (such as2,3-dichloro-5-methoxy-6-[3-(pyrrolidin-1-yl)propoxy]pyridine and2,3-dichloro-5-methoxy-6-[3-(pyrrolidin-1-yl)propoxy]pyrazine) can bemade from commercially available material, such as perchloropyrazine and2,3,5,6-tetrachloropyridine, through procedures known to those skilledin the art. Other compounds of formula 20 can also be made from startingmaterial, such as 5,6-dimethoxypyridin-2-amine,6-amino-5-chloro-3-(trifluoromethoxy)pyridin-2-ol,6-amino-5-chloro-2-(trifluoromethoxy)pyridin-3-ol,2,5-dichloro-6-methyl-nicotinonitrile, and 5,6-dichloronicotinonitrile.through procedures known to those skilled in the art.

Testing

The G9a inhibitory activity of the compounds of the present disclosurecan be tested using the in vitro assay described in Biological Examples1 below. The ability of the compounds of the disclosure to stimulatedfetal hemoglobin can be tested using the in vitro assay described inBiological Example 2 below.

Administration and Pharmaceutical Composition

In general, the compounds of this disclosure will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Therapeuticallyeffective amounts of compounds this disclosure may range from about 0.01to about 500 mg per kg subject body weight per day, which can beadministered in single or multiple doses. A suitable dosage level may befrom about 0.1 to about 250 mg/kg per day or about 0.5 to about 100mg/kg per day. A suitable dosage level may be about 0.01 to about 250mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 toabout 50 mg/kg per day. Within this range the dosage can be about 0.05to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.For oral administration, the compositions can be provided in the form oftablets containing about 1.0 to about 1000 milligrams of the activeingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150,200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of theactive ingredient. The actual amount of the compound of this disclosure,i.e., the active ingredient, will depend upon numerous factors such asthe severity of the disease to be treated, the age and relative healthof the subject, the potency of the compound being utilized, the routeand form of administration, and other factors.

In general, compounds of this disclosure will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules, including enteric coated or delayedrelease tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area, i.e., decreasing particlesize. For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a cross-linked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of in general, a compound of thisdisclosure in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the compound of thisdisclosure. Such excipient may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose and glycols.

Compressed gases may be used to disperse a compound of this disclosurein aerosol form. Inert gases suitable for this purpose are nitrogen,carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, edited by E. W. Martin(Mack Publishing Company, 20th ed., 2000).

The level of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt. %) basis, from about 0.01-99.99wt. % of a compound of this disclosure based on the total formulation,with the balance being one or more suitable pharmaceutical excipients.For example, the compound is present at a level of about 1-80 wt. %.

The compounds of this disclosure may be used in combination with one ormore other drugs in the treatment of diseases or conditions for whichcompounds of this disclosure or the other drugs may have utility. Suchother drug(s) may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent disclosure. When a compound of this disclosure is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of the present disclosure is preferred. However, thecombination therapy may also include therapies in which the compound ofthis disclosure and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present disclosure and the other active ingredients may be usedin lower doses than when each is used singly.

Accordingly, the pharmaceutical compositions of the present disclosurealso include those that contain one or more other drugs, in addition toa compound of the present disclosure.

The above combinations include combinations of a compound of thisdisclosure not only with one other drug, but also with two or more otheractive drugs. Likewise, a compound of this disclosure may be used incombination with other drugs that are used in the prevention, treatment,control, amelioration, or reduction of risk of the diseases orconditions for which a compound of this disclosure is useful. Such otherdrugs may be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a compound of thepresent disclosure. When a compound of this disclosure is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthis disclosure can be used. Accordingly, the pharmaceuticalcompositions of the present disclosure also include those that alsocontain one or more other active ingredients, in addition to a compoundof this disclosure. The weight ratio of the compound of this disclosureto the second active ingredient may be varied and will depend upon theeffective dose of each ingredient. Generally, an effective dose of eachwill be used.

Where the subject in need is suffering from or at risk of suffering fromcancer, the subject can be treated with a compound of this disclosure inany combination with one or more other anti-cancer agents and/oranti-cancer therapies. In some embodiments, the anti-cancer therapiescan be surgery and/or radiation therapy. In some embodiments, one ormore of the anti-cancer agents are proapoptotic agents. Examples ofanti-cancer agents include, but are not limited to, any of thefollowing: gossyphol, genasense, polyphenol E, Chlorofusin, alltrans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-relatedapoptosis-inducing ligand (TRAIL), 5-aza-2′-deoxycytidine, all transretinoic acid, doxorubicin, vincristine, etoposide, gemcitabine,imatinib (Gleevec™), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,Taxol™, also referred to as “paclitaxel”, which is a well-knownanti-cancer drug which acts by enhancing and stabilizing microtubuleformation, and analogs of Taxol™, such as docetaxel (Taxotere™).Compounds that have the basic taxane skeleton as a common structurefeature, have also been shown to have the ability to arrest cells in theG2-M phases due to stabilized microtubules and may be useful fortreating cancer in combination with the compounds described herein.

Further examples of anti-cancer agents for use in combination with acompound of this disclosure include inhibitors of mitogen-activatedprotein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901,ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002;Syk inhibitors; antibodies (e.g., rituxan); MET inhibitor such asforetinib, carbozantinib, or crizotinib; VEGFR inhibitor such assunitinib, sorafenib, regorafinib, lenvatinib, vandetanib,carbozantinib, or axitinib; EGFR inhibitor such as afatinib, brivanib,carbozatinib, erlotinib, gefitinib, neratinib, or lapatinib; PI3Kinhibitor such as XL147, XL765, BKM120 (buparlisib), GDC-0941, BYL719,IPI145, BAY80-6946. BEX235 (dactolisib), CAL101 (idelalisib),GSK2636771, or TG100-115; MTOR inhibitor such as rapamycin (sirolimus),temsirolimus, everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587,BEZ235, or GDC0349; MEK inhibitor such as AZD6244, trametinib, PD184352,pimasertinib, GDC-0973, or AZD8330; and proteasome inhibitor such ascarfilzomib, MLN9708, delanzomib, or bortezomib.

Other anti-cancer agents that can be employed in combination with acompound of this disclosure include Adriamycin; Dactinomycin; Bleomycin;Vinblastine; Cisplatin; acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine;gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;ifosfamide; ilmofosine; interleukin II (including recombinantinterleukin II, or Ril2), interferon alfa-2a; interferon alfa-2b;interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferongamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate;letrozole; leuprolide acetate; liarozole hydrochloride; lometrexolsodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; and zorubicin hydrochloride.

Other anti-cancer agents that can be employed in combination with acompound of the disclosure such as 20-epi-analogues of 1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;Bfgf inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;cladribine; clomifene analogues; clotrimazole; collismycin A;collismycin B; combretastatin A4; combretastatin analogue; conagenin;crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives;curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabineocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine;dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide;dexrazoxane; dexverapamil; diaziquone; didemnin B; didox;diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; docosanol; dolasetron; doxifluridine; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; fmasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline;lytic peptides; maitansine; mannostatin A; marimastat; masoprocol;maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;menogaril; merbarone; meterelin; methioninase; metoclopramide; MIFinhibitor; mifepristone; miltefosine; mirimostim; mismatched doublestranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; monoclonal antibody, human chorionic gonadotrophin;monophosphoryl lipid A+diethylstilbe cell wall sk; mopidamol; multipledrug resistance gene inhibitor; multiple tumor suppressor 1-basedtherapy; mustard anticancer agent; mycaperoxide B; mycobacterial cellwall extract; myriaporone; N-acetyldinaline; N-substituted benzamides;nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin;nartograstim; nedaplatin; nemorubicin; neridronic acid; neutralendopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxideantioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone;oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oralcytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillylalcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetinA; placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitors, microalgal; protein tyrosine phosphatase inhibitors;purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; R₁₁ retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived 1; sense oligonucleotides; signaltransduction inhibitors; signal transduction modulators; single chainantigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stem cell inhibitor; stem-cell division inhibitors;stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactiveintestinal peptide antagonist; suradista; suramin; swainsonine;synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide;tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium;telomerase inhibitors; temoporfin; temozolomide; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; totipotent stem cell factor; translation inhibitors;tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin;tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBCinhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor;urokinase receptor antagonists; vapreotide; variolin B; vector system,erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin;zilascorb; and zinostatin stimalamer.

Yet other anticancer agents that can be employed in combination with acompound of this disclosure include alkylating agents, antimetabolites,natural products, or hormones, e.g., nitrogen mustards (e.g.,mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan, etc.), nitrosoureas (e.g., carmustine,lomusitne, etc.), or triazenes (decarbazine, etc.). Examples ofantimetabolites include but are not limited to folic acid analog (e.g.,methotrexate), pyrimidine analogs (e.g., cytarabine, etc.), or purineanalogs (e.g., mercaptopurine, thioguanine, pentostatin, etc.).

Examples of natural products useful in combination with a compound ofthis disclosure include but are not limited to vinca alkaloids (e.g.,vincristine, etc.), epipodophyllotoxins (e.g., etoposide, etc.),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin, etc.), enzymes(e.g., L-asparaginase, etc.), or biological response modifiers (e.g.,interferon alpha, etc.).

Examples of alkylating agents that can be employed in combination acompound of this disclosure include, but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa, etc.), alkyl sulfonates (e.g., busulfan,etc.), nitrosoureas (e.g., carmustine, lomusitne, semustine,streptozocin, etc.), or triazenes (decarbazine, etc.). Examples ofantimetabolites include, but are not limited to folic acid analog (e.g.,methotrexate, etc.), pyrimidine analogs (e.g., fluorouracil,floxuridine, cytarabine, etc.), or purine analogs (e.g., mercaptopurine,thioguanine, pentostatin, etc.).

Examples of hormones and antagonists useful in combination a compound ofthis disclosure include, but are not limited to, adrenocorticosteroids(e.g., prednisone, etc.), progestins (e.g., hydroxyprogesteronecaproate, megestrol acetate and medroxyprogesterone acetate, etc.),estrogens (e.g., diethylstilbestrol and ethinyl estradiol, etc.),antiestrogen (e.g., tamoxifen, etc.), androgens (e.g., testosteronepropionate, fluoxymesterone, etc.), antiandrogen (e.g., flutamide, etc.)and gonadotropin releasing hormone analog (e.g., leuprolide, etc.).Other agents that can be used in the methods and compositions describedherein for the treatment or prevention of cancer include platinumcoordination complexes (e.g., cisplatin, carboblatin, etc.),anthracenedione (e.g., mitoxantrone, etc.), substituted urea (e.g.,hydroxyurea, etc.), methyl hydrazine derivative (e.g., procarbazine,etc.) and adrenocortical suppressant (e.g., mitotane, aminoglutethimide,etc.).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with an irreversible Btk inhibitor compound include withoutlimitation the following marketed drugs and drugs in development:Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10and NSC-376128), Mivobulin isethionate (also known as CI-980),Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296),ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1,Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9),Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356),Epothilones (such as Epothilone A, Epothilone B, Epothilone C (alsoknown as desoxyepothilone A or dEpoA)), Epothilone D (also referred toas KOS-862, dEpoB and desoxyepothilone B), Epothilone E, Epothilone F,Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D(also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone,Auristatin PE (also known as NSC-654663), Soblidotin (also known asTZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358(Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164(Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/KyowaHakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, alsoknown as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known asAVE-8062, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A), Vitilevuamide,Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1(Parker Hughes Institute, also known as DDE-261 and WHI-261), H10(Kansas State University), H16 (Kansas State University), Oncocidin A1(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute),Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1(Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes) and SSR-250411(Sanofi).

EXAMPLES

The following preparations of compounds of Formula (I) (Examples) andintermediates (References) are given to enable those skilled in the artto more clearly understand and to practice the present disclosure. Theyshould not be considered as limiting the scope of the disclosure, butmerely as being illustrative and representative thereof.

Reference 1 Synthesis of1-[3-(2-methoxy-5-nitrophenoxy)propyl]pyrrolidine (Intermediate I-1)

Into a 250-mL round-bottom flask was placed a mixture of2-methoxy-5-nitrophenol (5.00 g, 29.56 mmol, 1.00 eq.),N,N-dimethylformamide (60 mL), potassium carbonate (8.10 g, 58.61 mmol,2.00 eq.) and 1-(3-chloropropyl)pyrrolidine (5.99 g, 40.57 mmol, 1.10eq.). The resulted mixture was allowed to stir at 80° C. for 12 h. Thereaction mixture was cooled to rt, diluted with H₂O and extracted withethyl acetate thrice. The combined organic layers were dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel column with10% MeOH/CH₂Cl₂ as the eluent to provide1-[3-(2-methoxy-5-nitrophenoxy)propyl]pyrrolidine as yellow oil (4.80 g,58%). LCMS (ES) [M+1]⁺ m/z 281.

Reference 2 Synthesis of 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline(Intermediate I-2)

Into a 250-mL round-bottom flask, was placed a mixture of1-[3-(2-methoxy-5-nitrophenoxy)-propyl]pyrrolidine (Intermediate I-1)(4.80 g, 17.12 mmol, 1.00 eq.), methanol (100 mL) and 10% Pd/C (500 mg).The flask was degassed and purged with H₂ for 5 times. The mixture wasallowed to stir under H₂ atmosphere at rt for 4 h, and the solid wasfiltered off. Removal of organic solvents under reduced pressureprovided 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline as tan oil(4.10 g, 96%). LCMS (ES) [M+1]⁺ m/z 251.2.

Reference 3 Synthesis of1-[3-(4-bromo-2-methoxyphenoxy)propyl]pyrrolidine (Intermediate I-3)

Into a 1-L round-bottom flask, was placed a mixture of4-bromo-2-methoxyphenol (15.0 g, 73.88 mmol, 1.00 eq.),N,N-dimethylformamide (300 mL), 1-(3-chloropropyl)pyrrolidinehydrochloride (13.60 g, 73.88 mmol, 1.00 eq.), potassium iodide (12.26g, 73.88 mmol, 1.00 eq.) and potassium carbonate (20.4 g, 147.76 mmol,2.00 eq.). The resulting mixture was allowed to stir for 5 h at 70° C.The mixture was filtered and the filtrate was concentrated under reducedpressure. The residue was diluted with water and extracted with ethylacetate. The combined organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel column elutedwith dichloromethane/methanol (6/1) to provide1-[3-(4-bromo-2-methoxyphenoxy)propyl]pyrrolidine (Intermediate I-3) asa brown oil (18.5 g, 80%). LCMS (ES) [M+1]⁺ m/z 314.0.

Reference 4 Synthesis of1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine (IntermediateI-4)

Into a 500-mL 3-necked round-bottom flask, was placed a solution of1-[3-(4-bromo-2-methoxyphenoxy)propyl]pyrrolidine (Intermediate I-3)(18.0 g, 57.29 mmol, 1.00 eq.) in acetic acid (100 mL). To the stirringsolution was added HNO₃ (50 mL) dropwise at 15° C. The resultingsolution was allowed to stir for 3 h at 25° C. The reaction was thenquenched by the addition of ice water. The precipitate was collected byfiltration to provide1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine as a yellowsolid (18.1 g, 88%). LCMS (ES) [M+1]⁺ m/z 359.0.

Reference 5 Synthesis of1-{3-[4-(4,4-dimethyl-1,3,2-dioxaborolan-2-yl)-2-methoxy-5-nitrophenoxy]-propyl}pyrrolidine(Intermediate I-5)

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a mixture of1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)propyl]pyrrolidine (IntermediateI-4) (8.0 g, 22.27 mmol, 1.00 eq.), 1.4-dioxane (200 mL), BPD (8.51 g,33.51 mmol, 1.50 eq.), KOAc (4.38 g, 44.63 mmol, 2.00 eq.) andPd(dppf)Cl₂ (1.63 g, 2.23 mmol, 0.10 eq.). The resulting mixture wasallowed to stir under N₂ at 110° C. for 3 h. The mixture wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel column eluted with dichloromethane/methanol(10/1) to provide1-{3-[4-(4,4-dimethyl-1,3,2-dioxaborolan-2-yl)-2-methoxy-5-nitrophenoxy]propyl}pyrrolidine(Intermediate I-5) as a gray solid (6.1 g, 67%). LCMS (ES) [M+1]⁺ m/z407.2.

Reference 6 Synthesis of2-fluoro-4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (IntermediateI-6)

Step 1

Into a 250-mL round-bottom flask, was placed a mixture of2-fluoro-6-methoxyphenol (4.6 g, 32.36 mmol, 1.00 eq.), acetonitrile(150 mL), 3-(pyrrolidin-1-yl)propan-1-ol hydrochloride (10.73 g, 58.26mmol, 1.80 eq.), potassium carbonate (12.3 g, 89.00 mmol, 2.75 eq.) andpotassium iodide (9.67 g, 58.26 mmol, 1.80 eq.). The resulting mixturewas allowed to stir at 80° C. for 3 h. The solids were filtered off. Thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel column eluted with ethylacetate/petroleum ether (1/3) to provide1-[3-(2-fluoro-6-methoxyphenoxy)propyl]pyrrolidine as a yellow solid(4.35 g, 53%). LCMS (ES) [M+1]⁺ m/z 254.1.

Step 2

Into a 50-mL round-bottom flask placed in 0° C. ice bath was added1-[3-(2-fluoro-6-methoxy-phenoxy)propyl]pyrrolidine (4.35 g, 17.17 mmol,1.00 eq.). To the resulting mixture was added nitric acid (10 mL)slowly. The resulting solution was allowed to stir at room temperaturefor 1 h. The reaction mixture was poured into ice water (50 mL). The pHvalue of the solution was adjusted to 8 with sodium bicarbonate aqueoussolution (1.0 M). The resulting mixture was extracted with ethyl acetate(3×100 mL). The combined organic layers was washed with brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel columneluted with ethyl acetate/petroleum ether (1/5) to afford1-[3-(2-fluoro-6-methoxy-3-nitrophenoxy)propyl]pyrrolidine as a yellowoil (1.52 g, 30%). LCMS (ES) [M+1]⁺ m/z 299.2.

Step 3

Into a 100-mL round-bottom flask, was placed a mixture of1-[3-(2-fluoro-6-methoxy-3-nitrophenoxy)propyl]pyrrolidine (1.52 g, 5.10mmol, 1.00 eq.), methanol (30 mL) and 10% Pd/C (500 mg). The mixture wasdegassed and purged with hydrogen thrice. The resulting mixture wasallowed to stir under H₂ atmosphere at room temperature for 2 h. Thereaction mixture was diluted with MeOH (50 mL) and filtered through apad of celite. The filtrate was concentrated under reduced pressure toprovide 2-fluoro-4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline(Intermediate I-6) as a yellow oil (1.27 g, 93%). LCMS (ES) [M+1]⁺ m/z269.2.

Reference 7 Synthesis of1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1)

Into a 50-mL round-bottom flask was placed a mixture of8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-ol(Example 37 below) (346 mg, 1.01 mmol, 1.00 eq.) and POCl₃ (4.5 mL). Theresulted solution was allowed to stir at 100° C. for 2 h. After removalof volatiles under reduced pressure, the residue was poured into water.The mixture was adjusted with aqueous sodium bicarbonate solution (2 N)to pH=8, and extracted with CH₂Cl₂ thrice. The combined organic layerswere dried over anhydrous sodium sulfate. The solid was filtered off,and the solution was concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel column with 25%MeOH/CH₂Cl₂ (0.1% NH₄OH) as the eluent to provide the desired product(Intermediate II-1) as a yellow solid (214 mg, 59%). LCMS (ES) [M+1]⁺m/z 361.2.

Reference 8 Synthesis of6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2)

The title compound was made from2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-ol(Example 38 below) following a procedure similar as described for thesynthesis of Intermediate II-1 above. The crude product was purified byflash chromatography on silica gel column with 25% MeOH/CH₂Cl₂ (0.1%NH₄OH) as the eluent to provide the desired product as a brown solid.LCMS (ES) [M+1]⁺ m/z 375.2.

Reference 9 Synthesis of1-[3-({4-chloro-8-methoxy-2-methyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-3)

Step 1

Into a −78° C. solution of 3-methylcyclopent-2-en-1-one (14.40 g, 150.0mmol, 1.0 eq.) in tetrahydrofuran (200 mL) under N₂ atmosphere was addedlithium diisopropylamide (LDA) (150 mL, 2.0 M in THF, 300.0 mmol, 2.00eq.) over 20 min. The resulting solution was allowed to stir at −78° C.for 1 h. A solution of dimethyl carbonate (14.85 g, 165.0 mmol, 1.10eq.) in THF (150 mL) was added dropwise over 20 min. The resultingsolution was allowed to warm from −78° C. to rt and allowed to stir foradditional 3 h. The reaction mixture was poured into HCl aqueoussolution (1.0 N) at 0° C. The organic layer was separated. The waterlayer was back extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel column eluted with ethyl acetate/petroleumether (1/1) to provide methyl4-methyl-2-oxocyclopent-3-ene-1-carboxylate as a light brown oil (6.13g, 27%). LCMS (ES) [M+1]⁺ m/z 155.1.

Step 2

Into a 250-mL round-bottom flask, was placed a mixture of methyl4-methyl-2-oxocyclopent-3-ene-1-carboxylate (6.13 g, 39.81 mmol, 1.00eq.), methanol (100 mL) and 10% Pd/C (400 mg). The flask was flushedwith nitrogen thrice, followed by hydrogen twice. The mixture wasallowed to stir under hydrogen atmosphere at room temperature for 1 h.The solids were filtered off. The filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel column eluted with ethyl acetate/petroleum ether (1/2) toafford methyl 4-methyl-2-oxocyclopentane-1-carboxylate as a colorlessoil (3.87 g, 62%). LCMS (ES) [M+1]⁺ m/z 157.2.

Step 3

The title compound was made from methyl4-methyl-2-oxocyclopentane-1-carboxylate and4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2)following conditions similar as described in Example 37 below andReference 7 above, except that the final crude product was purified byflash chromatography on silica gel column eluted withdichloromethane/methanol (8/1) to provide the desired product as a lightbrown solid. LCMS (ES) [M+1]⁺ m/z 375.2.

Reference 10 Synthesis of1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-4)

The title compound was made from methyl4,4-dimethyl-2-oxocyclopentane-1-carboxylate (prepared according toliterature procedure reported in Organic Letters, 2004, Vol 6, No. 24,page 44411-4414) and 4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline(Intermediate I-2) following a procedure similar as described inReference 9 above, except that final crude product was purified by flashchromatography on silica gel column eluted with 10-20%MeOH/dichloromethane (0.1% NH₄OH) to provide the title product as alight brown solid. LCMS (ES) [M+1]⁺ m/z 389.2.

Reference 11 Synthesis of3-[({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)methyl]-1-methylpyrrolidine(Intermediate II-5)

Step 1

Into a 500-mL round-bottom flask, was placed a solution of methyl2-oxocyclopentanel-carboxylate (14.2 g, 99.89 mmol, 1.00 eq.), toluene(150 mL), ethane-1,2-diol (12.4 g, 199.78 mmol, 2.00 eq.) and TsOH (860mg, 4.99 mmol, 0.05 eq.). The solution was allowed to reflux overnight.The reaction mixture was cooled to room temperature, diluted with water(100 mL), and extracted with ethyl acetate thrice. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel column eluted with 25% ethyl acetate/petroleum ether (1/3) toprovide methyl 1,4-dioxaspiro[4.4]nonane-6-carboxylate as a colorlessoil (6.5 g. 35%).

Step 2

Into a 100-mL round-bottom flask, was placed a solution of methyl1,4-dioxaspiro[4.4]-nonane-6-carboxylate (6.5 g, 34.9 mmol, 1.00 eq.),methanol (60 mL), water (30 mL) and sodium hydroxide (2.78 g, 69.7.00mmol, 2.00 eq.). The resulting solution was allowed to stir at 80° C.for 2 h. The mixture was concentrated under reduced pressure. Theresidue was diluted with water and treated with saturated aqueousNaH₂PO₄ solution to pH=5˜6). The mixture was extracted with ethylacetate thrice. The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure to provide1,4-dioxaspiro[4.4]nonane-6-carboxylic acid as a white solid (3.94 g,66%).

Step 3

Into a 250-mL round-bottom flask purged and maintained under atmosphereof nitrogen, was placed a solution of 2-methoxy-5-nitrophenol (5.0 g,29.56 mmol, 1.00 eq.), dichloromethane (70 mL),(1-methylpyrrolidin-3-yl)methanol (6.8 g, 59.09 mmol, 2.00 eq.) and PPh3(15.5 g, 59.09 mmol, 2.00 eq.). To this stirring solution was added asolution of di-t-butyl azodicarboxylate (13.6 g, 59.09 mmol, 2.00 eq.)in dichloromethane (30 mL) dropwise at 0° C. under N₂. The resultingsolution was allowed to stir for 4 h at room temperature andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel column eluted with MeOH/CH₂Cl₂ (1/8) toprovide 3-(2-methoxy-5-nitrophenoxymethyl)-1-methylpyrrolidine as alight yellow solid (5.5 g, 70%). LCMS (ES) [M+1]⁺ m/z 267.1.

Step 4

Into a 250-mL round-bottom flask, was placed a mixture of3-(2-methoxy-5-nitrophenoxy-methyl)-1-methylpyrrolidine (5.5 g, 20.65mmol, 1.00 eq.), methanol (100 mL) and 10% Pd/C (500 mg). The flask wasflushed with nitrogen thrice followed by with hydrogen twice. Themixture was allowed to stir under H₂ atmosphere at rt overnight. Thesolids were filtered off. The filtrate was concentrated under reducedpressure to provide4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]aniline as a light brownoil (4.8 g, 98%). LCMS (ES) [M+1]⁺ m/z 237.2.

Step 5

Into a 250-mL round-bottom flask, was placed a solution of1,4-dioxaspiro[4.4]nonane-6-carboxylic acid (made in Step 2) (3.5 g,20.31 mmol, 1.00 eq.), N,N-dimethylformamide (50 mL),4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]aniline (4.8 g, 20.31mmol, 1.00 eq.), DIEA (5.24 g, 40.62 mmol, 2.00 eq.) and HATU (9.3 g,24.46 mmol, 1.20 eq.). The resulting solution was allowed to stir atroom temperature for 2 h. The crude reaction mixture was filtered andsubjected to purification on reverse phase preparative MPLC (Prep-C18,20-45 μM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of15-25% MeCN in water over a 10 min period, where both solvents contain0.05% TFA) to provideN-[4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]phenyl]-1,4-dioxaspiro[4.4]nonane-6-carboxamidein form of TFA salt as a yellow oil (3.4 g, 43%). LCMS (ES) [M-TFA+1]⁺m/z 390.2.

Step 6

Into a 250-mL round-bottom flask, was placed a solution ofN-[4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]phenyl]-1,4-dioxaspiro[4.4]nonane-6-carboxamide(3.4 g, 8.71 mmol, 1.00 eq.), MeCN (50 mL), aqueous HCl solution (17.5mL, 2.0 N, 34.9 mmol, 4.00 eq.). The resulting solution was allowed tostir at 50° C. for 5 h. The mixture was concentrated under reducedpressure to provide crudeN-[4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]phenyl]-2-oxocyclopentane-1-carboxamidehydrochloride salt as a yellow oil (3.05 g, 91%). LCMS (ES) [M+1]⁺ m/z347.2.

Step 7

Into a 100-mL round-bottom flask, was placed a solution ofN-[4-methoxy-3-[(1-ethylpyrrolidin-3-yl)methoxy]phenyl]-2-oxocyclopentane-1-carboxamidehydrochloride salt (3.05 g, 8.80 mmol, 1.00 eq.), toluene (30 mL), andpolyphosphoric acid (3 mL). The resulting mixture was allowed to stir at100° C. for 2 h. The mixture was concentrated under reduced pressure.The residue was diluted with water (100 mL) and basified with aqueousNaOH solution (2.0 N) to pH ˜8. The mixture was extracted withdichloromethane/methanol (10/1) thrice. The combined organic layers weredried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gelcolumn eluted with ethyl dichloromethane/methanol (8/1) to provide8-methoxy-7-[(1-methylpyrrolidin-3-yl)methoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-olas yellow oil (2.6 g, 90%). LCMS (ES) [M+1]⁺ m/z 328.2.

Step 8

Into a 100-mL round-bottom flask, was placed a solution of8-methoxy-7-[(1-methylpyrrolidin-3-yl)methoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-ol(2.6 g, 7.92 mmol, 1.00 eq.) and POCl₃ (30 mL). The resulting solutionwas allowed to stir at 100° C. for 2 h. The resulting mixture wasconcentrated under reduced pressure. The residue was diluted with 100 mLof dichloromethane, added into ice water (100 mL) dropwise and basifiedwith aqueous NaOH solution (2.0 N) to pH=˜9. The resulting mixture wasextracted with dichloromethane thrice. The combined organic layers weredried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gelcolumn eluted with ethyl dichloromethane/methanol (8/1) to provide thetitle product as a light yellow solid (1.35 g, 49%). LCMS (ES) [M+1]⁺m/z 347.1.

Reference 12 Synthesis of6-chloro-2-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-6)

The title compound was made from4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]aniline (prepared in thesynthesis of Intermediate II-5, step 4) following synthetic proceduredescribed for the synthesis of1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1), except that methyl 2-oxocyclohexane-1-carboxylatewas used in the place of methyl 2-oxocyclopentanel-carboxylate. LCMS(ES) [M+1]⁺ m/z 361.2.

Reference 13 Synthesis of1-[3-({4-chloro-6-fluoro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-7)

The title compound was made as described in Reference 11, Steps 5-8,except that 2-fluoro-4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline(Intermediate I-6) was used in the place of4-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]aniline. LCMS (ES) [M+1]⁺m/z 379.2.

Reference 14 Synthesis of1-[3-({1-benzyl-4-chloro-8-methoxy-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate III-1)

Step 1

Into a −20° C. solution of 1-benzylpyrrolidin-2-one (1.00 g, 5.71 mmol,1.00 eq.) in THF (20 mL) under N₂ was added lithium diisopropylamide(LDA) (6.3 mL, 2.0 M in THF, 12.6 mmol, 2.20 eq.) dropwise over 5 min.The resulting mixture was allowed to stir at −20° C. under N₂ for 1.5 h.Dry carbon dioxide gas was run through this solution at −20° C. for 0.5h. The reaction was then quenched by saturated aqueous NH₄Cl solution(6.3 mL) and then diluted with water. The pH was adjusted to 2-3 withconcentrated HCl. The resulting solution was extracted with EtOActhrice. The combined organic layers were dried over anhydrous sodiumsulfate. The solids were filtered off. The filtrate was concentratedunder reduced pressure to provide 1-benzyl-2-oxopyrrolidine-3-carboxylicacid as a colorless oil (700 mg, 56%). LCMS (ES) [M+1]⁺ m/z 220.2.

Step 2

Into a 40-mL vial charged with solution of1-benzyl-2-oxopyrrolidine-3-carboxylic acid (700 mg, 3.19 mmol, 1.00eq.) in dichloromethane (15 mL) was added4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) (839mg, 3.35 mmol, 1.05 eq.), diisopropylethylamine (825 mg, 6.38 mmol, 2.00eq.) and HATU (1.46 g, 3.84 mmol, 1.20 eq.). The resulting mixture wasallowed to stir at rt for 0.5 h. The solution was diluted withdichloromethane, washed with saturated aqueous NaHCO₃. The organic layerwas separated, dried over anhydrous sodium sulfate and concentratedunder reduced pressure to provide1-benzyl-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-2-oxopyrrolidine-3-carboxamideas a brown oil (1.15 g, 80%). LCMS (ES) [M+1]⁺ m/z 452.4.

Step 3

Into a 50-mL round-bottom flask, was placed a mixture of1-benzyl-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-2-oxopyrrolidine-3-carboxamide(1.15 g, 2.55 mmol, 1.00 eq.) and POCl₃ (23 mL). The resulting mixturewas allowed to stir at 110° C. under condenser for 3 h. The reaction wasconcentrated under reduced pressure and quenched with ice water (20 mL).The pH value of the solution was adjusted to 8 with saturated aqueousNaHCO₃. The resulting solution was extracted with a mixed solution ofdichloromethane/MeOH (V/V=10/1) thrice. The organic layers werecombined, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel column eluted with petroleum ether/THF (5% TEA) (1/4) toprovide1-[3-({1-benzyl-4-chloro-8-methoxy-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate III-1) as a brown solid (600 mg, 52%). LCMS (ES) [M+1]⁺m/z 452.2.

Reference 15 Synthesis of1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate III-2)

Step 1

To a solution of 5,5-dimethylpyrrolidin-2-one (2.0 g, 17.67 mmol, 1.00eq.) in N,N-dimethylformamide (50 mL) was added sodium hydride (848 mg,21.20 mmol, 1.20 eq.) in portions at 0° C. The resulting solution wasallowed to stir under N₂ at 0° C. for 0.5 h. To the above solution wasadded a solution of p-methoxybenzyl chloride (3.32 g, 21.20 mmol, 1.20eq.) in N,N-dimethylformamide (10 mL) dropwise over 5 min. The solutionwas allowed to stir at room temperature for 16 h before being quenchedby water. The mixture was extracted with EtOAc thrice. The combinedorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified byreverse phase preparative MPLC (Prep-C18, 20-45 μM, 120 g, TianjinBonna-Agela Technologies; gradient elution of 40-60% MeCN in water overa 8 min period, where both solvents contain 0.1% formic acid (FA)) toprovide 1-[(4-methoxyphenyl)methyl]-5,5-dimethylpyrrolidin-2-one as ayellow oil (2.87 g, 70%). LCMS (ES) [M+1]⁺ m/z 234.1.

Step 2

Into a 100-mL 3-necked round-bottom flask, was placed a solution of1-[(4-methoxyphenyl)-methyl]-5,5-dimethylpyrrolidin-2-one (2.00 g, 8.57mmol, 1.00 eq.) in dry THF (40 mL). To the above solution was added asolution of t-BuLi (12.3 mL, 1.6 M in pentane, 19.7 mmol, 2.3 eq.)dropwise with stirring at −78° C. The resulting solution was allowed tostir for 1.5 h at −78° C. under N₂. Dry CO₂ gas was allowed to runthrough the above solution at −78° C. for 0.5 h. After warming to 0° C.,the reaction mixture was quenched by saturated aqueous NH₄Cl solutionand diluted with water. The pH was adjusted to 2-3 with concentrated HCland then extracted with EtOAc thrice. The combined organic layers weredried over anhydrous sodium sulfate and concentrated under reducedpressure to provide1-[(4-methoxyphenyl)methyl]-5,5-dimethyl-2-oxopyrrolidine-3-carboxylicacid as a colorless oil (2.10 g, 87%). LCMS (ES) [M+1]⁺ m/z 278.2.

Step 3

Into a 50-mL round-bottom flask, was placed a mixture of1-[(4-methoxyphenyl)methyl]-5,5-dimethyl-2-oxopyrrolidine-3-carboxylicacid (2.10 g, 7.57 mmol, 1.00 eq.),4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) (1.90g, 7.59 mmol, 1.00 eq.), dichloromethane (30 mL), DIEA (1.96 g, 15.17mmol, 2.00 eq.) and HATU (3.46 g, 9.10 mmol, 1.20 eq.). The resultingsolution was allowed to stir at rt for 0.5 h. The solution was dilutedwith dichloromethane and washed with saturated aqueous NaHCO₃ solution.The organic layer was separated, dried over anhydrous sodium sulfate,concentrated under reduced pressure and purified by silica gel columnchromatography with petroleum ether/THF (5% TEA) (1/2) as the eluents toprovideN-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1-[(4-methoxyphenyl)methyl]-5,5-dimethyl-2-oxopyrrolidine-3-carboxamideas a brown oil (2.10 g, 54%). LCMS (ES) [M+1]⁺ m/z 510.2.

Step 4

Into a 100-mL round-bottom flask, was placed a mixture ofN-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1-[(4-methoxyphenyl)methyl]-5,5-dimethyl-2-oxopyrrolidine-3-carboxamide(1.50 g, 2.94 mmol, 1.00 eq.) and POCl₃ (30 mL). The resulting solutionwas allowed to stir under reflux for overnight. The solution wasconcentrated under reduced pressure. To the residue was added ice waterand the pH value was adjusted to 8 with NaHCO₃ (solid). The mixture wasextracted with a mixed solution of 10% MeOH/dichloromethane (3×30 mL).The combined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel column with petroleum ether/THF (1/2)(mixed with 5% TEA) to provide1-[3-([4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl]oxy)propyl]pyrrolidine(Intermediate III-2) as a brown oil (700 mg, 61%). LCMS (ES) [M+1]⁺ m/z390.2.

Reference 16 Synthesis of1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-3)

Step 1

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed a mixture of1-{3-[4-(4,4-dimethyl-1,3,2-dioxaborolan-2-yl)-2-methoxy-5-nitrophenoxy]propyl}pyrrolidine(Intermediate I-5) (2.8 g, 6.89 mmol, 1.00 eq.), 1,4-dioxane (100 mL),methyl 2-chloropyridine-3-carboxylate (1.77 g, 10.32 mmol, 1.50 eq.),potassium carbonate (1.9 g, 13.75 mmol, 2.00 eq.), and Pd(PPh₃)₄ (797mg, 0.69 mmol, 0.10 eq.). The resulting mixture was allowed to stir at100° C. under N₂ for 4 h. The mixture was concentrated under reducedpressure. The residue was purified by flash chromatography on silica gelcolumn eluted with 10% MeOH/CH₂Cl₂ to provide methyl2-[5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl]pyridine-3-carboxylate(1.6 g, 56%) as a gray solid. LCMS (ES) [M+1]⁺ m/z 416.1.

Step 2

Into a 100-mL round-bottom flask, was placed a mixture of methyl2-[5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl]pyridine-3-carboxylate(1.3 g, 3.13 mmol, 1.00 eq.), ethanol (50 mL), water (5 mL), Iron powder(1.75 g, 31.30 mmol, 10.00 eq.) and NH₄Cl (830 mg, 15.52 mmol, 5.00eq.). The resulting mixture was allowed to stir at 90° C. for 6 h. Thesolids were filtered off. The filtrate was concentrated under reducedpressure. The residue was purified by flash chromatography on silica gelcolumn eluted with 10-15% MeOH/CH₂Cl₂ to provide9-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-5H,6H-benzo[h]1,6-naphthyridin-5-oneas a red solid (780 mg, 71%). LCMS (ES) [M+1]⁺ m/z 354.1.

Step 3

Into a 50-mL round-bottom flask, was placed9-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-5H,6H-benzo[h]1,6-naphthyridin-5-one(740 mg, 2.09 mmol, 1.00 eq.) and POCl₃ (10 mL). The resulting solutionwas allowed to stir at 100° C. for 6 h. The resulting mixture wasconcentrated under reduced pressure. To the residue was added ice water.The pH value of the mixture was adjusted to 7 with Na₂CO₃ (solid). Theresulting mixture was concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel column eluted with10-15% MeOH/dichloromethane to provide1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-3) as a light yellow solid (430 mg, 55%). LCMS (ES)[M+1]⁺ m/z 372.1.

Reference 17 Synthesis of1-[3-({5-chloro-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl}oxy)-propyl]pyrrolidine(Intermediate III-4)

The title compound was made following a synthetic procedure similar asdescribed in Reference 16 above except that methyl2-chloro-6-methylpyridine-3-carboxylate was used in the place of methyl2-chloropyridine-3-carboxylate. LCMS (ES) [M+1]⁺ m/z 386.2.

Reference 18 Synthesis of1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine(Intermediate III-5)

Step 1

Into a 0° C. mixture of sodium hydride (7.78 g, 60% in mineral oil,194.58 mmol, 1.10 eq.) in THF (200 mL) under N₂ was added a solution ofazepan-2-one (12.0 g, 106.1 mmol, 1.00 eq.) in THF (100 mL) dropwiseover 30 min. The resulting mixture was allowed to stir for 30 min at 0°C. To this resulting mixture was added a solution of p-methoxybenzylchloride (18.2 g, 116.21 mmol, 1.10 eq.) in THF (100 mL) dropwise over20 min. The resulting solution was allowed to stir at room temperaturefor 3 h, and was quenched with water under N₂ atmosphere. The resultingmixture was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel column eluted with ethylacetate/petroleum ether (1/1) to provide1-[(4-methoxyphenyl)methyl]azepan-2-one as a light yellow oil (7.2 g,29%). LCMS (ES) [M+1]⁺ m/z 234.1.

Step 2

Into a 500-mL 3-necked round-bottom flask, was placed a solution of1-[(4-methoxyphenyl)-methyl]azepan-2-one (7.3 g, 31.29 mmol, 1.00 eq.)in THF (150 mL). To the resulting solution at −78° C. under N₂ was addedlithium diisopropylamide (LDA) (39.2 mL, 2 M,78.3 mmol, 2.5 eq.)dropwise. The resulting solution was allowed to stir at −78° C. for 30min. To the above solution was added a solution of dimethyl carbonate(5.6 g, 62.6 mmol, 2.0 eq.) in THF (50 mL) at −78° C. The resultingmixture was allowed to warm to room temperature and stirred for 2 h. Thereaction was then quenched by saturated aqueous NH₄Cl, extracted with105 MeOH/CH₂Cl₂ twice. The combined organic layers were concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel column eluted with ethyl acetate/petroleum ether (1/1) toprovide methyl 1-[(4-methoxyphenyl)methyl]-2-oxoazepane-3-carboxylate asyellow oil (6.8 g, 75%). LCMS (ES) [M+1]⁺ m/z 292.1.

Step 3

Into a 250-mL round-bottom flask, was placed a mixture of methyl1-[(4-methoxyphenyl)-methyl]-2-oxoazepane-3-carboxylate (6.7 g, 23.00mmol, 1.00 eq.), methanol (100 mL) and sodium hydroxide (2.76 g, 69.00mmol, 3.00 eq.). The resulting solution was allowed to stir for 3 h atroom temperature. The pH of the reaction mixture was adjusted to ˜6 withaqueous HCl (1.0 M) and then concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel column elutedwith 10% MeOH/dichloromethane to provide1-[(4-methoxyphenyl)methyl]-2-oxoazepane-3-carboxylic acid a yellowsolid (6.1 g, 96%). LCMS (ES) [M+1]⁺ m/z 278.1.

Step 4

Into a 1-L round-bottom flask, was placed a mixture of1-[(4-methoxyphenyl)methyl]-2-oxoazepane-3-carboxylic acid (6.1 g, 22.00mmol, 1.00 eq.), CH₂Cl₂ (300 mL),4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) (6.1g, 24.13 mmol, 1.10 eq.), N,N-diisopropylethylamine (DIEA) (14.2 g,109.87 mmol, 5.00 eq.) and HATU (9.2 g, 24.20 mmol, 1.10 eq.). Theresulting solution was allowed to stir at rt for 4 h. The solution waswashed with H₂O (2×50 mL) and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel column using10% MeOH/dichloromethane as the eluents to provideN-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1-[(4-methoxyphenyl)-methyl]-2-oxoazepane-3-carboxamideas yellow oil (8.1 g, 72%). LCMS (ES) [M+1]⁺ m/z 510.3.

Step 5

Into a 100-mL round-bottom flask, was placed a solution ofN-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1-[(4-methoxyphenyl)methyl]-2-oxoazepane-3-carboxamide(2.5 g, 4.91 mmol, 1.00 eq.) and POCl₃ (30 mL). The resulting solutionwas allowed to stir at 100° C. for 10 h. The mixture was concentratedunder reduced pressure. The residue was diluted with ice water (30 mL).The reaction mixture was treated with potassium carbonate (solid) tillpH-99 and extracted with a mixed solution of 20% dichloromethane/80%MeOH thrice. The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel column eluted with 10-20%MeOH/dichloromethane/methanol (0.1% NH₄OH) to provide the title compound(Intermediate III-5) as a yellow solid (0.9 g, 47%). LCMS (ES) [M+1]⁺m/z 390.2.

Reference 19 Synthesis of1-[3-({5-chloro-9-methoxy-1H,2H,4H-pyrano[3,4-c]quinolin-8-yl}oxy)-propyl]pyrrolidine(Intermediate III-6)

Step 1

Into a 250-mL round-bottom flask, was placed a mixture of methyl4-oxo-tetrahydro-2H-pyran-3-carboxylate (5.64 g, 35.69 mmol, 1.00 eq.),toluene (100 mL), ethane-1,2-diol (4.43 g, 71.39 mmol, 2.0 eq.), p-TsOH(615 mg, 3.57 mmol, 0.10 eq.). The resulting mixture was allowed to stirfor 24 h with reflux under a dean stark trap. The mixture wasconcentrated and the residue was purified by a silica gel column elutedwith 20% ethyl acetate/petroleum ether to afford methyl1,4,8-trioxaspiro[4.5]decane-6-carboxylate as a colorless oil (6.7 g,93%). LCMS (ES) [M+1]⁺ m/z 203.1.

Step 2

Into a mixture of methyl 1,4,8-trioxaspiro[4.5]decane-6-carboxylate(6.70 g, 33.16 mmol, 1.00 eq.) in MeOH/THF/H₂O (50 mL/50 mL/50 mL) wasadded NaOH (2.65 g, 66.32 mmol, 2.0 eq.). The resulting solution wasallowed to stir at room temperature for 4 h. The organic solvents wereremoved under reduced pressure. The resulting mixture was acidified topH 5˜6 with aqueous HCl (1.0 N), extracted with ethyl acetate thrice Thecombined organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to provide1,4,8-trioxaspiro[4.5]decane-6-carboxylic acid as white solid (3.97 g,64%). LCMS (ES) [M−1]⁻ m/z 187.1.

Step 3

The title compound was made following a procedure similar as describedabove in Reference 11, Steps 5-8 but using1,4,8-trioxaspiro[4.5]decane-6-carboxylic acid and4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2).Thefinal crude product was purified by flash chromatography on silica gelcolumn eluted with 10% MeOH/CH₂Cl₂ (0.1% NH₄OH) to afford the titlecompound as a white solid. LCMS (ES) [M+1]⁺ m/z 377.2.

Reference 20 Synthesis of1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate III-7)

The title compound was prepared from4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) andethyl 4-oxotetrahydrofuran-3-carboxylate following a synthetic sequencessimilar as described for the synthesis of8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-olin Example 37 below and (Intermediate II-1 above, except that finalcrude product was purified by reverse phase preparative MPLC (Prep-C18,20-45 μM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of25-45% MeCN in water over a 12 min period, where both solvents contain0.1% formic acid (FA)) to provide the desired compound of1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate III-7) as formate salt. LCMS (ES) [M-FA+1]⁺ m/z 363.2.

Reference 21 Synthesis of8-(benzyloxy)-6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate III-8)

Step 1

Into a 250-mL round-bottom flask was placed a solution of4-(benzyloxy)cyclohexan-1-one (10.0 g, 48.96 mmol, 1.00 eq.) in THF (100mL). The flask was placed into ice bath, to the solution was addedsodium hydride (2.35 g, 60% dispersion in mineral oil, 58.75 mmol, 1.20eq.) and dimethyl carbonate (6.62 g, 73.49 mmol, 1.50 eq.) under N2atmosphere. The resulting mixture was allowed to stir in an oil bath at80° C. for 2 h. After cooling the reaction to room temperature, thereaction mixture was quenched with water and extracted with ethylacetate thrice. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure to provide methyl 5-(benzyloxy)-2-oxocyclohexane-1-carboxylateas a colorless oil (12.5 g, 97%). LCMS (ES) [M+1]⁺ m/z 263.1.

Step 2

Into a 250-mL round-bottom flask, was placed a mixture of methyl5-(benzyloxy)-2-oxo-cyclohexane-1-carboxylate (9.18 g, 35.00 mmol, 1.00eq.), ethane-1,2-diol (21.7 g, 349.62 mmol, 10.00 eq.), p-TsOH (1.81 g,10.50 mmol, 0.30 eq.) and toluene (100 mL). The resulting solution wasallowed to stir at 125° C. for 16 h with Dean-Stark trap to removewater. The reaction mixture was allowed to cool for rt and concentratedunder reduced pressure. The remaining residue was diluted with 200 mL ofH₂O, and the mixture was extracted with of ethyl acetate thrice. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to provide thedesired crude product of methyl8-(benzyloxy)-1,4-dioxaspiro[4.5]decane-6-carboxylate as a yellow oil(10.8 g).

Step 3

Into a 250-mL round-bottom flask, was placed a solution of methyl8-(benzyloxy)-1,4-dioxaspiro[4.5]decane-6-carboxylate (5.50 g, 17.95mmol, 1.00 eq.), methanol (100 mL), water (10 mL) and sodium hydroxide(3.59 g, 89.75 mmol, 5.00 eq.) in portions. The resulting solution wasallowed to stir at 60° C. for 2 h and then concentrated under reducedpressure. The residue was diluted with 100 mL of H₂O. The pH value ofthe solution was adjusted to 5 with aqueous HCl (2.0 N). The mixture wasextracted with 10% MeOH/CH₂Cl₂ five times. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under reducedpressure to provide the desired crude product of8-(benzyloxy)-1,4-dioxaspiro[4.5]decane-6-carboxylic acid as yellow oil(4.75 g, 91%). LCMS (ES) [M+1]⁺ m/z 293.1.

Step 4

Into a 250-mL round-bottom flask, was placed a mixture of8-(benzyloxy)-1,4-dioxaspiro-[4.5]decane-6-carboxylic acid (4.50 g,15.39 mmol, 1.00 eq.), N,N-dimethylformamide (60 mL),4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (3.85 g, 15.34 mmol,1.00 eq.), N,N-diisopropylethylamine (DIEA) (5.96 g, 46.12 mmol, 3.00eq.) and HATU (8.78 g, 23.09 mmol, 1.50 eq.). The mixture was allowed tostir at rt for 1.0 h. The resulting mixture was diluted with H₂O andextracted with ethyl acetate thrice. The combined organic layers werewashed with water and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to provide8-(benzyloxy)-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1,4-dioxaspiro[4.5]decane-6-carboxamideas yellow oil (5.13 g, 64%) of. LCMS (ES) [M+1]⁺ m/z 525.3.

Step 5

Into a 0° C. mixture of8-(benzyloxy)-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-1,4-dioxaspiro[4.5]decane-6-carboxamide(5.13 g, 9.78 mmol, 1.00 eq.) in THF (50 mL) was added aq. HCl (37% 15mL) dropwise over 5 min. The solution was allowed to stir at rt for 0.5h. The resulting mixture was then concentrated under reduced pressure.The residue was diluted with 100 mL of H₂O. The pH value of the solutionwas adjusted to 8 with aq. NaOH (2.0 N). The resulting mixture wasextracted with 10% MeOH/CH₂Cl₂ four times. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under reducedpressure to provide5-(benzyloxy)-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-2-oxocyclohexane-1-carboxamideas brown crude oil (4.56 g, 97%). LCMS (ES) [M+1]⁺ m/z 481.3.

Step 6

Into a 50-mL round-bottom flask, was placed a mixture of5-(benzyloxy)-N-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-2-oxocyclohexane-1-carboxamide(4.56 g, 9.49 mmol, 1.00 eq.) and POCl₃ (15 mL). The resulting solutionwas allowed to stir for at 100° C. for 2 hand then concentrated underreduced pressure. To the residue was added 100 mL of ice water. The pHvalue of the solution was adjusted to 8 with aq. NaOH (2.0 N), and themixture was extracted with 10% MeOH/CH₂Cl₂ four times. The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedunder reduced pressure to provide crude-(benzyloxy)-6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate III-8) as brown crude oil (4.12 g, 90%). LCMS (ES) [M+1]⁺m/z 481.2.

Reference 22 Synthesis of1-[3-({5-chloro-9-methoxy-3-methyl-1H,2H,3H,4H-benzo[c]2,7-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-9)

Step 1

Into a −78° C. solution of 1-tert-butyl 3-methyl4-oxopiperidine-1,3-dicarboxylate (2.0 g, 7.78 mmol, 1.00 eq.),in CH₂Cl₂(50 mL) was added N,N-diisopropylethylamine (DIEA) (2.0 g, 15.56 mmol,2.0 eq.) followed by Tf₂O (3.28 g, 11.67 mmol, 1.50 eq.) dropwise. Theresulting mixture was allowed to warm to rt and to stir for 3 h. Thereaction mixture was quenched by H₂O and extracted with CH₂Cl₂. Thecombined organic layers were dried over the anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel column eluted with 25% ethylacetate/petroleum ether to provide1-(tert-butyl)-3-methyl-4-(((trifluoromethyl)-sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylateas yellow oil (2.4 g, 80%). LCMS (ES) [M+1]⁺ m/z 390.1.

Step 2

Into a 50-mL round-bottom flask was placed a mixture of1-(tert-butyl)-3-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate(479 mg, 1.23 mmol, 1.00 eq.), dioxane (8 mL), water (2 mL),1-{3-[4-(4,4-dimethyl-1,3,2-dioxaborolan-2-yl)-2-methoxy-5-nitrophenoxy]propyl}pyrrolidine(Intermediate I-5) (500 mg, 1.23 mmol, 1.0 eq.), Pd(PPh₃)₄ (141 mg,0.123 mmol, 0.1 eq.) and Na₂CO₃ (326 mg, 3.07 mmol, 2.5 eq.). Themixture was allowed to stir at reflux under N₂ for overnight. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel column eluted with50% ethyl acetate/petroleum ether to provide 1-(tert-butyl)3-methyl-4-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,6-dihydropyridine-1,3(2H)-dicarboxylateas brown solid (216 mg, 34%). LCMS (ES) [M+1]⁺ m/z 520.3.

Step 3

Into a 50-mL round-bottom flask, was placed a mixture of 1-(tert-butyl)3-methyl-4-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,6-dihydropyridine-1,3(2H)-dicarboxylate(216 mg, 0.415 mmol, 1.00 eq.), MeOH (10 mL) and 10% Pd/C (50 mg). Themixture was degassed and purged with hydrogen. The resulting mixture wasallowed to stir under H₂ atmosphere at rt for overnight. The reactionmixture was diluted with MeOH (10 mL) and filtered through a small padof celite. The filtrate was concentrated under reduced pressure toprovide tert-butyl5-hydroxy-9-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,2-dihydrobenzo[c][2,7]naphthyridine-3(4H)-carboxylateas brown oil (200 mg, 95%). LCMS (ES) [M+1]⁺ m/z 458.3.

Step 4

Into a 25-mL round-bottom flask was placed tert-butyl5-hydroxy-9-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,2-dihydrobenzo[c][2,7]naphthyridine-3(4H)-carboxylate(200 mg, 0.436 mmol, 1.00 eq.) followed by POCl₃ (10 mL). The resultingsolution was allowed to stir at 110° C. for 2 h. The organic volatileswere reduced under reduced pressure. To the residue was added 5 mL ofice/water and the pH value was adjusted to 8 with Na₂CO₃ (solid). Theprecipitate was collected through filtration to afford5-chloro-9-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridine(180 mg, 91%). LCMS (ES) [M+1]⁺ m/z 376.1.

Step 5

Into a 25-mL round-bottom flask, were placed a mixture of5-chloro-9-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,2,3,4-tetrahydrobenzo[c][2,7]naphthyridine(180 mg, 0.478 mmol, 1.00 eq.), acetonitrile (5 mL), water (2 mL), CH₂O(37% (aq.), 0.2 mL) and NaBH₃CN (74.6 mg, 1.18 mmol, 2.5 eq.). Theresulting mixture was allowed to stir at rt for 4 h. The mixture wasfiltered and subjected to reverse phase preparative MPLC (Prep-C18,20-45 μM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of20-40% MeCN in water over a 7 min period, where both solvents contain0.1% formic acid (FA)) to provide the title compound (IntermediateIII-9) in form of formate salt as a brown solid (110 mg, 59%). LCMS (ES)[M+1]⁺ m/z 390.3.

Reference 23 Synthesis of1-[3-({5-chloro-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-10)

Step 1

To a solution of 3-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid(50.0 g, 230.4 mmol, 1.00 eq.) in dichloromethane (1200 mL) was added2,2-dimethyl-1,3-dioxane-4,6-dione (33.1 g, 230.4 mmol, 1.00 eq.), EDCI(48.7 g, 253.4 mmol, 1.10 eq.) and 4-dimethylaminopyridine (30.9 g,253.4 mmol, 1.10 eq.). The resulting solution was allowed to stir for atroom temperature for 16 h. The solution was washed with H₂O (3×200 mL),dried over anhydrous sodium sulfate and concentrated under vacuum toprovide tert-butyl4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methyl-4-oxobutan-2-ylcarbamateas an off-white solid (60.5 g, 77%). LCMS (ES) [M−1]⁻ m/z 342.1.

Step 2

To a 0° C. solution of tert-butylN-[4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methyl-4-oxobutan-2-yl]carbamate(60.5 g, 176.2 mmol, 1.00 eq.) in AcCN/AcOH (600 mL, V/V=3:1) was addedNaBH₄ (20.1 g, 528.6 mmol, 3.00 eq.) in portions over 15 min. Theresulting solution was stirred at rt for 16 h. The mixture wasconcentrated under vacuum. The residue was subjected to reversepreparative HPLC (Prep-C18, 20-45 μM, 120 g, Tianjin Bonna-AgelaTechnologies; gradient elution of 40% MeCN in water to 71% MeCN in waterover a 9 min period, where both solvents contain 0.1% TFA) to providetert-butyl4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methylbutan-2-ylcarbamateas a white solid (35.5 g, 61%). LCMS (ES) [M−1]⁻ m/z 328.1.

Step 3

To a solution of tert-butylN-[4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-methylbutan-2-yl]carbamate(35.5 g, 107.9 mmol, 1.00 eq.) in methanol (150 mL) was added dioxane(150 mL) which was freshly saturated with hydrochloride (gas). Theresulting solution was allowed to stir rt for 16 h. The solution wasconcentrated under vacuum to provide dimethyl2-(3-amino-3-methylbutyl)malonate hydrochloride as a white solid (23.5g, 86%). LCMS (ES) [M+1]⁺ m/z 218.1.

Step 4

Into a 250-mL round-bottom flask, was placed a solution of methanol (150mL), 1,3-dimethyl 2-(3-amino-3-methylbutyl)propanedioate hydrochloride(23.5 g, 92.9 mmol, 1.00 eq.) and TEA (28.1 g, 278.7 mmol, 3.00 eq.).The resulting solution was allowed to stir at 65° C. for 24 h. Thevolatiles were removed under vacuum. The residue was re-dissolved inwith EtOAc (200 mL), washed with brine (2×50 mL), and dried overanhydrous sodium sulfate. Revoal of the organic solvents under reducedpressure provided methyl 6,6-dimethyl-2-oxopiperidine-3-carboxylate as awhite solid (20.3 g, crude). LCMS (ES) [M+1]⁺ m/z 186.2.

Step 5

To a solution of methyl 6,6-dimethyl-2-oxopiperidine-3-carboxylate (10.0g, 54.0 mmol 1.00 eq.) in a mixed solution of THF/MeOH/H₂O (100 mL,V/V/V=5:5:1) was added lithium hydroxide monohydrate (4.54 g, 108.0mmol, 2.00 eq.). The resulting mixture was allowed to stir at rt for 16h. The mixture was concentrated under vacuum. The residue was dilutedwith H₂O (20 mL), acidified carefully with aqueous HCl (1.0 N) to pH ˜4,and the resulting mixture was extracted with CH₂Cl₂/MeOH (V/V=5:1, 3×50mL). The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under vacuum to provide6,6-dimethyl-2-oxopiperidine-3-carboxylic acid as a white solid (7.8 g,84%). LCMS (ES) [M+1]⁺ m/z 172.2.

Step 6

To a solution of 6,6-dimethyl-2-oxopiperidine-3-carboxylic acid (8.0 g,46.7 mmol, 1.00 eq.) in N,N-dimethylformamide (150 mL) was added TEA(12.0 g, 116.8 mmol, 2.50 eq.),4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (14.0 g, 56.0 mmol, 1.20eq.), HOBt (9.5 g, 70.0 mmol, 1.50 eq.) and EDCI (13.4 g, 70.0 mmol,1.50 eq.). The resulting solution was stirring for 16 h at roomtemperature. The crude reaction mixture was filtered and subjected toreverse preparative HPLC (Prep-C18, 20-45 μM, 120 g, Tianjin Bonna-AgelaTechnologies; gradient elution of 5% MeCN in water to 30% MeCN in waterover a 7 min period, where both solvents contain 0.1% TFA) over multipleruns to provideN-(4-methoxy-3-(3-(pyrrolidin-1-yl)propoxy)phenyl)-6,6-dimethyl-2-oxopiperidine-3-carboxamideas a white solid (16.8 g, 89%). LCMS (ES) [M+1]⁺ m/z 404.2.

Step 7

Into a 250-mL sealed tube, was placed a solution of POCl₃ (100 mL) andN-[4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]phenyl]-6,6-dimethyl-2-oxopiperidine-3-carboxamide(10.0 g, 24.8 mmol, 1.00 eq.). The resulting solution was stirred at170° C. for 7 h and then concentrated under reduced pressure. Theresidue was pured into ice water (50 mL) and carefully basified withaqueous solution NaOH (2.0 N) (pH ˜8) and extracted with CH₂Cl₂/MeOH(V/V=5:1, 3×200 mL). The combined organic layers were dried overanhydrous sodium sulfate and concentrated under vacuum. The crude wasdiluted with DMF (50 mL), filtered and subjected to reverse preparativeHPLC (Prep-C18, 20-45 μM, 120 g, Tianjin Bonna-Agela Technologies;gradient elution of 40% MeCN in water to 71% MeCN in water over a 7 minperiod, where both solvents contain 0.1% TFA) over multiple runs toprovide the title compound as an off-white solid. The compound wasfurther purified by a silica gel column eluted with DCM/MeOH (4/1) toprovide the title compound as a brown solid (0.5447 g, 5%). ¹H NMR (300MHz, CD₃OD-d₄) δ 7.20 (s, 1H), 6.80 (s, 1H), 4.75 (s, 1H), 4.17 (t,J=5.9 Hz, 2H), 4.00 (s, 3H), 3.25-3.10 (m, 6H), 2.92 (t, J=6.6 Hz, 2H),2.39-2.33 (m, 2H), 2.07-2.02 (m, 5H), 1.83 (t, J=6.6 Hz, 2H), 1.37 (s,6H). LCMS (ES) [M+1]⁺ m/z 404.2.

Reference 24 Synthesis of1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]piperidine(Intermediate III-11)

The title compound was made from 2-methoxy-5-nitrophenol and1-(3-chloropropyl)piperidine hydrogen chloride following a proceduresimilar as described above for Intermediate II-1. The crude product waspurified by a silica gel column eluted with dichloromethane/methanol(10/1) to provide the title compound as light brown solid. LCMS (ES)[M+1]⁺ m/z 375.1.

Reference 25 Synthesis of1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]-3,3-dimethylpyrrolidine(Intermediate III-12)

Step 1

Into a 500-mL round-bottom flask, was placed a mixture of2-methoxy-5-nitrophenol (10.0 g, 59.17 mmol, 1.00 eq.), CH₃CN (200 mL),1-chloro-3-iodopropane (18.11 g, 88.76 mmol, 1.50 eq.) and potassiumcarbonate (16.33 g, 118.34 mmol, 2.00 eq.). The resulting mixture wasallowed to stir at 85° C. for 3 h and cooled to room temperature. Thesolids were filtered off and the filtrate was concentrated under vacuum.The residue was purified by a silica gel column eluted with ethylacetate/petroleum ether (1/2) to provide2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene as an off-white solid (7.86g, 54%).

Step 2

Into a 250-mL round-bottom flask, was placed a mixture of2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene (5.0 g, 20.41 mmol, 1.00eq.), CH₃CN (100 mL), 3,3-dimethylpyrrolidine hydrochloride (2.76 g,20.41 mmol, 1.00 eq.), Cs₂CO₃ (13.31 g, 40.82 mmol, 2.00 eq.) and KI(6.78 g, 40.82 mmol, 2.00 eq.). The resulting mixture was allowed tostir for 16 h at 80° C. and cooled to room temperature. The solids werefiltered off, and the filtrate was concentrated under vacuum. Theresidue was purified by a silica gel column eluted withdichloromethane/methanol (10/1) to provide1-[3-(2-methoxy-5-nitrophenoxy)propyl]-3,3-dimethylpyrrolidine as ayellow solid (5.21 g, 83%). LCMS (ES) m/z 309.1 [M+1]⁺.

Step 3˜Step 6

The title compound was made from1-[3-(2-methoxy-5-nitrophenoxy)propyl]-3,3-dimethylpyrrolidine followinga procedure similar as described for the synthesis of Intermediate II-1above. The crude product was purified by a silica gel column eluted withdichloromethane/methanol (10/1) to provide the title compound as ayellow solid. LCMS (ES) m/z 389.2 [M+1]⁺.

Reference 26 Synthesis of[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]dimethylamine(Intermediate III-13)

The title compound was made from 2-methoxy-5-nitrophenol and3-chloro-N,N-dimethylpropan-1-amine hydrogen chloride following aprocedure similar as described above for the synthesis of IntermediateII-1. The crude product was purified by column chromatography on silicagel eluted with dichloromethane/methanol (10/1) to provide the titlecompound as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): 7.33 (s, 1H),7.14 (s, 1H), 4.15 (t, J=6.0 Hz, 2H), 3.93 (s, 3H), 3.32-3.27 (m, 4H),3.05 (t, J=6.9 Hz, 2H), 2.44-2.39 (m, 2H), 2.18 (s, 6H), 1.96-1.91 (m,2H). LCMS (ES) [M+1]⁺ m/z 335.1.

Reference 27 Synthesis of[3-([4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy)propyl]diethylamine(Intermediate III-14)

The title compound was made from 2-methoxy-5-nitrophenol and3-chloro-N,N-diethylpropan-1-amine following a procedure similar asdescribed above for the synthesis of Intermediate II-1. The crudeproduct was purified by column chromatography on silica gel eluted withdichloromethane/methanol (10/1) to provide the title compound as anoff-white solid. ¹H NMR (300 MHz, DMSO-d₆): 7.32 (s, 1H), 7.09 (s, 1H),4.17 (t, J=6.0 Hz, 2H), 3.92 (s, 3H), 3.25 (t, J=7.2 Hz, 2H), 3.02 (t,J=7.5 Hz, 2H), 2.80-2.55 (m, 6H), 2.25-2.15 (m, 2H), 2.02-1.91 (m, 2H),1.10-0.98 (m, 6H). LCMS (ES) [M+1]⁺ m/z 363.2.

Reference 28 Synthesis of4-[3-([4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy)propyl]morpholine(Intermediate III-15)

The title compound was made from 2-methoxy-5-nitrophenol and4-(3-chloropropyl)morpholine following a procedure similar as describedfor the synthesis of Intermediate II-1 above. The crude product waspurified by column chromatography on silica gel eluted withdichloromethane/methanol (10/1) to provide the title compound as anoff-white solid. The crude product was purified by column chromatographyon silica gel eluted with dichloromethane/methanol (10/1) to provide thetitle compound as a light yellow solid. LCMS (ES) [M+1]⁺ m/z 377.2.

Example 1 Synthesis of8-methoxy-N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and methyl amine (2.0 N in THF), following aprocedure similar as described in n Example 3 below, except that thecrude product was purified by reverse preparative HPLC (Prep-C18, 5 μMOBD column, 19×250 mm, waters; gradient elution of 0-40% MeCN in waterover a 20 min period, where both solvents contain 0.1% formic acid, flowrate: 20 mL/min) to provide the title compound as brown syrup. LCMS (ES)[M+1]⁺ m/z 356.2.

Example 2 Synthesis of2-methoxy-N-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amineformate

The title compound was made from6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2) and methyl amine (2.0 N in THF), following aprocedure similar as described in Example 3 below, except the reactionwas conducted in microwave reactor at 80° C. for 2 h. The crude productwas purified by reverse preparative HPLC (Prep-C18, 5 μM OBD column,19×250 mm, waters; gradient elution of 0-40% MeCN in water over a 20 minperiod, where both solvents contain 0.1% formic acid, flow rate: 20mL/min) to provide the title compound as brown syrup. LCMS (ES) [M+1]⁺m/z 370.2.

Example 3 Synthesis of8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta-[c]quinolin-4-aminetrifluoroacetate

A mixture of1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]-pyrrolidine(Intermediate II-1) (250 mg, 0.69 mmol, 1.00 eq.), 1,4-dioxane (5 mL),and t-BuONa (331 mg, 3.45 mmol, 5.00 eq.) in a microwave reaction vialwas purged with N₂ for 5 min. To the solution was added propan-2-amine(285 mg, 4.83 mol, 7.00 eq.), and 3rd Generation BrettPhos pre-catalyst(64 mg, 0.07 mmol, 0.10 eq.). After being purged with N₂ for additional2 min, the resulting solution was sealed and subjected to microwavereactor (120° C., 1.5 h). The reaction mixture was allowed to cool to rtand quenched with H₂O. After removal of the volatiles under reducedpressure, the residue was re-dissolved in DMSO, filtered and subjectedto reverse preparative HPLC (Prep-C18, 5 mM XBridge column, 19×150 mm,waters; gradient elution of 10-25% MeCN in water over a 10 min period,where both solvents contain 0.1% trifluoroacetic acid (TFA)) to providethe title compound as brown oil (70 mg, 15%). LCMS (ES) [M+1]⁺ m/z 384.

Example 4 Synthesis of2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)ethan-1-oltrifluoroacetatetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and 2-aminoethane-1-ol, following a proceduresimilar as described in Example 3 above. The crude product was purifiedby reverse preparative HPLC (Prep-C18, 5 mM XBridge column, 19×150 mm,waters; gradient elution of 10-25% MeCN in water over a 10 min period,where both solvents contain 0.1% trifluoroacetic acid (TFA)) to providethe title compound as brown oil. LCMS (ES) [M+1]⁺ m/z 386.3.

Example 5 Synthesis of8-methoxy-N-(2-phenylethyl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

Into a 50-mL round-bottom flask maintained under atmosphere of drynitrogen was placed1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) (150 mg, 0.42 mmol, 1.00 eq.), 1,4-dioxane (10 mL),2-phenylethan-1-amine (103 mg, 0.85 mmol, 2.00 eq.), Cs₂CO₃ (277 mg,0.85 mmol, 2.00 eq.), Pd₂(dba)₃CHCl₃ (43 mg, 0.05 mmol, 0.10 eq.) and2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (26 mg, 0.04 mmol, 0.10 eq.)subsequently. The resulting mixture was allowed to stir at 100° C. underN₂ for overnight. The crude reaction mixture was cooled to rt, andtreated with water (5 mL). After removal of volatiles, the residue wasre-dissolved in DMSO, filtered and subjected to purification on reversephase preparative HPLC (Prep-C18, 5 μM SunFire column, 19×150 mm,Waters; gradient elution of 5-20% MeCN in water over a 1 min period and20%-43% MeCN in water over a 6.5 min period, where both solvents contain0.1% trifluoroacetic acid (TFA)) to provide the title compound as ayellow semi-solid (102.0 mg, 36%). LCMS (ES) [M+1]⁺ m/z 446.3.

Example 6 Synthesis of8-methoxy-2-methyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

Into a 50-mL round-bottom flask, was placed a mixture of propan-2-amine(248 mg, 4.20 mmol, 2.00 eq.), 1,4-dioxane (20 mL), sodium sulfate (895mg, 6.30 mmol, 3.00 eq.), ^(t)BuONa (604 mg, 6.30 mol, 3.00 eq.), 3rdGeneration BrettPhos precatalyst (381 mg, 0.42 mmol, 0.20 eq.) and1-[3-({4-chloro-8-methoxy-2-methyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-3) (787 mg, 2.10 mmol, 1.00 eq.). The resulting mixturewas allowed to stir at 90° C. under N₂ for 2 h. The mixture was cooledto rt, filtered and subjected to purification on reverse phasepreparative HPLC (Prep-C18, 5 μM SunFire column, 19×150 mm, Waters;gradient elution of 17-34% MeCN in water over a 7 min period, where bothsolvents contain 0.1% FA) to provide the title compound as a yellowsolid (102.8 mg, 12.3%). LCMS (ES) [M+1]⁺ m/z 398.4.

Example 7 Synthesis ofN-cyclobutyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and cyclobutylamine, following a procedure similaras described in Example 5 above, except that reaction solution wasallowed to stir at 100° C. under N₂ atmosphere for 16 h. The crudeproduct was purified by reverse preparative HPLC (Prep-C18, 5 μM XBridgecolumn, 19×150 mm, Waters; gradient elution of 8-24% MeCN in water overa 7 min period, where both solvents contain 0.1% FA) to provide thetitle compound as an off-white solid (153.8 mg, 19%). LCMS (ES) [M+1]⁺m/z 396.4.

Example 8 Synthesis ofN-cyclopentyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and cyclopentylamine, following the proceduredescribed above in Example 3, except that the reaction was conducted inmicrowave reactor at 130° C. for 2.5 h. The crude reaction solution wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel column eluted with 10% MeOH/CH₂Cl₂. Thedesired fractions were combined and concentrated under reduced pressure.The resulting crude product was further purified by prep-HPLC (SunFirePrep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of36-49% MeCN in water over a 8 min period, where both solvents contain0.05% TFA) to provide the title compound as an off-white solid (522.9mg, 49%). LCMS (ES) [M+1]⁺ m/z 410.4.

Example 9 Synthesis of8-methoxy-N-methyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

Into a 50-mL seal tube was placed a mixture of8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine(Example 3) (110 mg, 0.29 mmol, 1.00 eq.), ethanol (10 mL), CH₂O (aq.37%) (0.23 mL, 2.90 mmol, 10.00 eq.) and NaBH₃CN (54 mg, 0.86 mmol, 3.00eq.). The resulting solution was allowed to stir at 120° C. for 16 h.The crude reaction mixture was filtered and subjected to purification onreverse phase preparative HPLC (Prep-C18, 5 μM SunFire column, 19×150mm, Waters; gradient elution of 20-32% MeCN in water over a 9.5 minperiod, where both solvents contain 0.1% trifluoroacetic acid (TFA)) toprovide the title compound as a yellow solid (18.5 mg, 10%). LCMS (ES)[M+1]⁺ m/z 398.2.

Example 10 Synthesis of1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}pyrrolidineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and pyrrolidine, following the procedure describedabove in Example 3, except that reaction solution was left stirring at100° C. under N₂ atmosphere for 14 h. The crude reaction mixture wasfiltered and subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of5-22% MeCN in water over a 7 min period, where both solvents contain0.1% formic acid (FA)) to provide the title compound as a dark greensolid (119.3 mg, 65%). LCMS (ES) [M+1]⁺ m/z 396.2.

Example 11 Synthesis of8-methoxy-7-[(1-methylpyrrolidin-3-yl)methoxy]-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

Into a 40-mL vial was placed3-[({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)methyl]-1-methylpyrrolidine(Intermediate II-5) (300 mg, 0.86 mmol, 1.00 eq.), 1,4-dioxane (6 mL),propan-2-amine (255 mg, 4.31 mmol, 5.00 eq.), t-BuONa (165 mg, 1.72mmol, 2.00 eq.) and 3^(rd) Brettphos precatalyst (78.4 mg, 0.086 mmol,0.10 eq.) subsequently. The resulting mixture was purged with N₂ for 5min, sealed and allowed to stir at 90° C. for 2 h. The crude reactionmixture was concentrated under reduced pressure. The remaining residuewas re-dissolved in DMSO, filtered and subjected to purification onreverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150mm, Waters; gradient elution of 19-24% MeCN in water over a 7 minperiod, where both solvents contain 0.1% trifluoroacetic acid (TFA)) toprovide the title compound as brown oil (203.1 mg, 39%). LCMS (ES)[M+1]⁺ m/z 370.4.

Example 12 Synthesis of2-methoxy-N-(oxan-4-yl)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-aminetrifluoroacetate

The title compound was made from6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2) and tetrahydro-2H-pyran-4-amine as described abovein Example 3. The crude product was purified by reverse preparative HPLC(Prep-C18, 5 mM XBridge column, 19×150 mm, waters; gradient elution of10-33% MeCN in water over a 10 min period, where both solvents contain0.1% trifluoroacetic acid (TFA)) to provide the title compound as brownsyrup. LCMS (ES) [M+1]⁺ m/z 440.3.

Example 13 Synthesis of2-methoxy-N-(propan-2-yl)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amineformate

The title compound was made from6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2) and propan-2-amine following a procedure asdescribed above in Example 3. The crude product was purified by reversepreparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters;gradient elution of 5-30% MeCN in water over a 7 min period, where bothsolvents contain 0.1% formic acid (FA)) to provide the title compound asbrown syrup. LCMS (ES) [M+1]⁺ m/z 398.3.

Example 14 Synthesis ofN-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}acetamidetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and acetamide, following a procedure similar asdescribed in Example 5 above except that crude product was purified byreverse preparative HPLC (Prep-C18, 20-45 μM, 120 g, Tianjin Bonna-AgelaTechnologies; gradient elution of 15-45% MeCN in water over a 9 minperiod, where both solvents contain 0.1% trifluoroacetic acid (TFA)) toprovide the title compound as brown syrup. LCMS (ES) [M+1]⁺ m/z 384.2.

Example 15 Synthesis of2-({2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-yl}amino)ethan-1-olformate

The title compound was made from6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2) and 2-aminoethane-1-ol, following a proceduresimilar as described in Example 3 above, except that the crude productwas purified by reverse preparative HPLC (Prep-C18, 5 μM OBD column,19×250 mm, waters; gradient elution of 0-25% MeCN in water over a 20 minperiod, where both solvents contain 0.1% formic acid (FA), flow rate: 20mL/min) to provide the title compound as brown syrup. LCMS (ES) [M+1]⁺m/z 400.2.

Example 16 Synthesis of(1r,3r-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclobutan-1-oltrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and trans-3-aminocyclobutane-1-ol, following aprocedure similar as described in Example 3 above, except that the crudeproduct was purified by reverse preparative HPLC (Prep-C18, 20-45 μM,120 g, Tianjin Bonna-Agela Technologies; gradient elution of 6-31% MeCNin water over a 9 min period, where both solvents contain 0.1%trifluoroacetic acid (TFA)) to provide the title compound as a brownsyrup. LCMS (ES) [M+1]⁺ m/z 412.3.

Example 17 Synthesis of8-methoxy-N-[(3R)-oxolan-3-yl]-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and (R)-tetrahydrofuran-3-amine, following aprocedure similar as described in Example 3, except that reactionmixture was allowed to stir at 100° C. under N₂ for 16 h. The crudeproduct was subjected to reverse phase preparative HPLC (Prep-C18, 5 μMXBridge column, 19×150 mm, Waters; gradient elution of 11-28% MeCN inwater over a 7 min period, where both solvents contain 0.1% formic acid(FA)) to provide the title compound as a light yellow solid (138.4 mg,33%). LCMS (ES) [M+1]⁺ m/z: 412.4.

Example 18 Synthesis of8-methoxy-N-[(3S)-oxolan-3-yl]-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and (S)-tetrahydrofuran-3-amine, following aprocedure similar as described in Example 3 above, except that reactionmixture was allowed to stir at 100° C. under N₂ for 16 h. The crudeproduct was subjected to reverse phase preparative HPLC (Prep-C18, 5 μMXBridge column, 19×150 mm, Waters; gradient elution of 11-28% MeCN inwater over a 7 min period, where both solvents contain 0.1% formic acid(FA)) to provide the title compound as a brown syrup. LCMS (ES) [M+1]⁺m/z 412.4.

Example 19 Synthesis ofN-cyclopropyl-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amineformate

The title compound was made from6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2) and cyclopropanamine following a procedure similaras described in Example 3 above, except that the crude product waspurified by reverse preparative HPLC (Prep-C18, 5 μM XBridge column,19×150 mm, Waters; gradient elution of 10-35% MeCN in water over a 7 minperiod, where both solvents contain 0.1% formic acid (FA)) to providethe title compound as a brown syrup. LCMS (ES) [M+1]⁺ m/z 396.2.

Example 20 Synthesis of2-methoxy-6-(methylamino)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-8-olformate

The title compound was made from8-(benzyloxy)-6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate III-8) and methylamine (2.0 M in THF), following aprocedure similar as described in Example 61, except that the crudeproduct was purified by reverse preparative HPLC (Prep-C18, 5 μM OBDcolumn, 19×250 mm, waters; gradient elution of 0-40% MeCN in water overa 20 min period, where both solvents contain 0.1% formic acid, flowrate: 20 mL/min) to provide the title compound as a brown syrup. LCMS(ES) [M+1]⁺ m/z 386.2.

Example 21 Synthesis of1-[3-({8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidinetrifluoroacetate

Into a 25-mL round-bottom flask, was placed a mixture of1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) (250 mg, 0.69 mmol, 1.00 eq.), N,N-dimethylformamide(10 mL), t-BuONa (331 mg, 3.45 mmol, 5.00 eq.), propan-2-amine (285 g,4.83 mol, 7.00 eq.), Pd₂(dba)₃ (321 mg, 0.35 mmol, 0.50 eq.) and PCy₃(26 mg, 0.069 mmol, 0.10 eq.). The resulting solution was allowed tostir for 5 h at 90° C. under N₂. The mixture was filtered and subjectedto reverse preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm,Waters; gradient elution of 8-32% MeCN in water over a 7 min period,where both solvents contain 0.1% trifluoroacetic acid (TFA)) to providethe title compound as a brown oil (66.4 mg, 22%). LCMS (ES) [M+1]⁺ m/z327.3.

Example 22 Synthesis of8-methoxy-N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin-4-aminetrifluoroacetate

Step 1

Into a 8 mL seal tube under N₂ was added a mixture of1-[3-({1-benzyl-4-chloro-8-methoxy-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate III-1) (300 mg, 0.66 mmol, 1.00 eq.), 1.4-dioxane (4 mL),MeNH₂ (1.6 mL, 2.0 M in THF, 3.32 mmol, 5.00 eq.), t-BuONa (127 mg, 1.32mmol, 2.00 eq.) and 3rd Brettphos precatalyst (30 mg, 0.0332 mmol, 0.05eq.) subsequently. The vial was sealed and the solution was allowed tostir at 90° C. for 1 h. The resulting mixture was concentrated and theresidue was purified by flash chromatography on silica gel column with33% petroleum ether in THF (both containing 5% trimethylamine) toprovide the desired product of1-benzyl-8-methoxy-N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin-4-amineas a light brown solid. LCMS (ES) [M+1]⁺ m/z 447.2.

Step 2

To a solution of1-benzyl-8-methoxy-N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin-4-amine(115 mg, 0.26 mmol, 1.00 eq.) in MeOH (3 mL) and CH₃CO₂H (0.1 mL) wasadded 10% Pd/C (10 mg). The mixture was degassed and purged with H₂ forseveral times. The resulting mixture was allowed to stir at roomtemperature under hydrogen atmosphere for 3 h. The reaction mixture wasdiluted with MeOH (5 mL), filtered and subjected to purification onreverse phase preparative HPLC (Prep-C18, 5 μM SunFire column, 19×150mm, Waters; gradient elution of 13-35% MeCN in water over a 7 minperiod, where both solvents contain 0.1% trifluoroacetic acid (TFA)) toprovide the title compound as a light brown oil (32.7 mg, 22%). LCMS(ES) [M+1]⁺ m/z 357.2.

Example 23 Synthesis of8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2c]-quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-({1-benzyl-4-chloro-8-methoxy-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate III-1), as described in Example 22, Step 1 above, exceptthat propan-2-amine was used in place of methylamine. The crude productwas purified by reverse preparative HPLC (Prep-C18, 5 μM SunFire column,19×150 mm, Waters; gradient elution of 5-40% MeCN in water over a 7 minperiod, where both solvents contain 0.1% trifluoroacetic acid (TFA)) toprovide the title compound as a light brown oil (22.5 mg, 13%). LCMS(ES) [M+1]⁺ m/z 385.2.

Example 24 Synthesis of8-methoxy-N,2,2-trimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-([4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl]oxy)propyl]pyrrolidine(Intermediate III-2) and methylamine (1.0 N in THF), following aprocedure similar as described in Example 22 Step 1 above, except thatthe crude reaction mixture was filtered and subjected to purification onreverse phase preparative HPLC (Prep-C18, 5 μM SunFire column, 19×150mm, Waters; gradient elution of 15-32% MeCN in water over a 7 minperiod, where both solvents contain 0.1% trifluoroacetic acid (TFA)) toprovide the title compound as a brown oil (85.5 mg, 18%). LCMS (ES)[M+1]⁺ m/z 385.2.

Example 25 Synthesis of8-methoxy-2,2-dimethyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-pyrrolo[3,2-c]quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-([4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl]oxy)propyl]pyrrolidine(Intermediate III-2) and propan-2-amine, following a procedure similaras described in Example 22, Step 1 above. The crude reaction mixture wasdiluted with N,N-dimethylformamide, filtered and subjected topurification on reverse phase preparative HPLC (Prep-C18, 5 μM SunFirecolumn, 19×150 mm, Waters; gradient elution of 19-35% MeCN in water overa 7 min period, where both solvents contain 0.1% trifluoroacetic acid(TFA)) to provide the title compound as a brown oil (118.1 mg, 24%).LCMS (ES) [M+1]⁺ m/z 413.2.

Example 26 Synthesis of9-methoxy-N-methyl-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-5-amineformate

Step 1

Into a 40-mL sealed tube maintained with an inert atmosphere of nitrogenwas added mixture of1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-3) (210 mg, 0.56 mmol, 1.00 eq.), Cs₂CO₃ (368 mg, 1.13mmol, 2.00 eq.), 1,4-dioxane (10 mL), MeNH₂/THF (1M in THF, 1.7 mL, 1.68mmol, 3.00 eq.), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (35 mg,0.06 mmol, 0.10 eq.), Pd₂(dba)₃CHCl₃ (59 mg, 0.06 mmol, 0.10 eq.). Theresulting mixture was allowed to stir at 100° C. under N₂ for 16 h. Themixture was concentrated under reduced pressure and the residue waspurified by flash chromatography on silica gel column eluted with 10-20%MeOH/CH₂Cl₂ to provide the desired product of9-methoxy-N-methyl-8-[3-(pyrrolidin-1-yl)propoxy]benzo[h]1,6-naphthyridin-5-amineas a yellow oil (116 mg, 56%). LCMS (ES) [M+1]⁺ m/z 367.2.

Step 2

Into a 50-mL round-bottom flask, was placed a mixture of9-methoxy-N-methyl-8-[3-(pyrrolidin-1-yl)propoxy]benzo[h]1,6-naphthyridin-5-amine(111 mg, 0.30 mmol, 1.00 eq.), methanol (10 mL) and 10% Pd/C (50 mg).The mixture was degassed and purged with hydrogen for three times. Theresulting mixture was allowed to stir at rt for 6 h. The mixture wasdiluted with MeOH (50 mL) and the solids were filtered off through a padof celite. The filtrate was concentrated under reduced pressure. Theresidue was dissolved in N,N-dimethylformamide (5 mL), filtered andsubjected to purification on reverse phase preparative HPLC (Prep-C18, 5μM XBridge column, 19×150 mm, Waters; a gradient elution of 5% MeCN inwater over a 1.5 min period and 5-20% MeCN in water over a 7 min period,where both solvents contain 0.1% formic acid (FA)) to provide the titlecompound as a light yellow solid (57.1 mg, 41%). LCMS (ES) [M+1]⁺ m/z371.1.

Example 27 Synthesis of9-methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-5-aminetrifluoroacetate

The title compound was made from1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-3) following a procedure similar as described above inExample 26, except that propan-2-amine was used in place of methylaminein Step 1. The final crude product was purified by reverse preparativeHPLC (Prep-C18, 5 μM SunFire column, 19×150 mm, Waters; gradient elutionof 5% MeCN in water over a 1 min period and 5-25% MeCN in water over a 7min period where both solvents contain 0.1% trifluoroacetic acid (TFA))to provide the title compound as a yellow oil. LCMS (ES) [M+1]⁺ m/z399.2.

Example 28 Synthesis of1-[3-({9-methoxy-5-methyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidinetrifluoroacetate

Step 1

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a mixture of1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridin-8-yl}oxy)-propyl]pyrrolidine(Intermediate III-3) (220 mg, 0.59 mmol, 1.00 eq.), 1,4-dioxane (20 mL),trimethyl-1,3,5,2,4,6-trioxatriborinane (598 mg, 50%/W in THF, 2.37mmol, 4.00 eq.), Cs₂CO₃ (580 mg, 1.78 mmol, 3.00 eq.) and Pd(PPh₃)₄ (69mg, 0.06 mmol, 0.10 eq.) subsequently. The resulting mixture was allowedat 110° C. under N₂ for 3 h, and then concentrated under reducedpressure. The residue was dissolved in DMSO, filtered and subjected topurification by flash chromatography on silica gel column eluted with10-15% MeOH/CH₂Cl₂ to provide the desired product of1-[3-([9-methoxy-5-methylbenzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidineas a yellow solid (155 mg, 75%). LCMS (ES) [M+1]⁺ m/z 352.2.

Step 2

Into a 50-mL round-bottom flask, was placed a solution of1-[3-([9-methoxy-5-methylbenzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine(150 mg, 0.43 mmol, 1.00 eq.), methanol (10 mL), 10% Pd/C (15 mg). Themixture was degassed and purged with H₂ for several times and thenstirred at rt under H₂ atmosphere (balloon) for 4 h. The crude reactionmixture was filtered and subjected to purification on reverse phasepreparative HPLC (Prep-C18, 5 μM SunFire column, 19×150 mm, Waters;gradient elution of 12-25% MeCN in water over a 8 min period, where bothsolvents contain 0.1% trifluoroacetic acid (TFA)) to provide the titlecompound as a yellow oil (20.4 mg, 8%). LCMS (ES) [M+1]⁺ m/z 356.2.

Example 29 Synthesis of9-methoxy-N,2-dimethyl-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-5-amineformate

Step 1

Into a seal tube was placed a solution of1-[3-({5-chloro-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-4) (200 mg, 0.52 mmol, 1.00 eq.), DMSO (10 mL) andCH₃NH₂ (5.2 mL, 1M in THF, 5.2 mmol, 10.00 eq.). The resulting solutionwas sealed and allowed to stir at 120° C. overnight. The reactionsolution was diluted with water and extracted with a mixed solution of20% MeOH/CH₂Cl₂. The organic layers were combined, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel column eluted with 5-20%MeOH/CH₂Cl₂ to provide the desired product of9-methoxy-N,2-dimethyl-8-[3-(pyrrolidin-1-yl)propoxy]benzo[h]1,6-naphthyridin-5-amineas a yellow solid (125 mg, 63%). LCMS (ES) [M+1]⁺ m/z 381.3.

Step 2

Into a 50-mL round-bottom flask, was placed a solution of9-methoxy-N,2-dimethyl-8-[3-(pyrrolidin-1-yl)propoxy]benzo[h]1,6-naphthyridin-5-amine(125 mg, 0.33 mmol, 1.00 eq.), methanol (10 mL) and 10% Pd/C (15 mg).The resulting mixture was degassed and purged with H₂ for several time,and allowed to stir at rt under H₂ atmosphere for 6 h. The crudereaction mixture was filtered and subjected to purification on reversephase preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm,Waters; gradient elution of 5-17% MeCN in water over a 7 min period,where both solvents contain 0.1% formic acid (FA)) to provide the titlecompound as a white solid (23.3 mg, 16%). LCMS (ES) [M+1]⁺ m/z 385.3.

Example 30 Synthesis of9-methoxy-2-methyl-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-5-amineformate

The title compound was made from1-[3-({5-chloro-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-4), following the procedure described in Example 29above, except that propan-2-amine was used in place of methyl amine. Thefinal crude product was purified by reverse preparative HPLC (Prep-C18,5 μM XBridge column, 19×150 mm, Waters; gradient elution of 5-25% MeCNin water over a 7.5 min period, where both solvents contain 0.1% formicacid (FA)) to provide the title compound as a white solid (33.1 mg,24%). LCMS (ES) [M+1]⁺ m/z 413.3.

Example 31 Synthesis of1-[3-({9-methoxy-2,5-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidinetrifluoroacetate

The title compound was made from1-[3-({5-chloro-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-4), following a procedure similar as described inExample 28 above. The final crude product was purified by reversepreparative HPLC (Prep-C18, 5 μM SunFire column, 19×150 mm, Waters;gradient elution of 5-35% MeCN in water over a 7 min period, where bothsolvents contain 0.1% trifluoroacetic acid (TFA)) to provide the titlecompound as a yellow semi-solid (31.4 mg, 17%). LCMS (ES) [M+1]⁺ m/z370.2.

Example 32 Synthesis of1-[3-({5-cyclopropyl-9-methoxy-2-methyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidinetrifluoroacetate

Step 1

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was added1-[3-({5-chloro-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]-pyrrolidine(Intermediate III-4) (210 mg, 0.54 mmol, 1.00 eq.), 1,4-dioxane (20 mL),cyclopropylboronic acid (94 mg, 1.09 mmol, 2.00 eq.), Cs₂CO₃ (356 mg,1.09 mmol, 2.00 eq.) and Pd(PPh₃)₄ (63 mg, 0.05 mmol, 0.10 eq.)subsequently. The resulting mixture was allowed to stir at 110° C. underN₂ for 4 h. The resulting mixture was concentrated under reducedpressure. The residue was purified by flash chromatography on silica gelcolumn eluted with 5-20% MeOH/CH₂Cl₂ to provide the desired product of1-[3-([5-cyclopropyl-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidineas a yellow solid (135 mg, 63%). LCMS (ES) [M+1]⁺ m/z 392.2.

Step 2

Into a rt solution of1-[3-([5-cyclopropyl-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine(95 mg, 0.24 mmol, 1.00 eq.) in 1,4-dioxane (5 mL) was added a solutionof 1,4-dioxane (1 mL) saturated with HCl (gas). The resulting solutionwas allowed to stir at rt for 1 h and then concentrated under reducedpressure to provide the corresponding HCl salt of1-[3-([5-cyclopropyl-9-methoxy-2-methylbenzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine.To a 50-mL round-bottom flask was placed a solution of the above HClsalt in methanol (10 mL) and 10% Pd/C (10 mg). The resulting mixture wasdegassed and purged with H₂ for several times and was then allowed tostir at rt under H₂ atmosphere for 6 h. The crude reaction mixture wasfiltered and subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM SunFire column, 19×150 mm, Waters; gradient elution of20-33% MeCN in water over a 7.5 min period, where both solvents contain0.1% trifluoroacetic acid (TFA)) to provide the title compound as a darkyellow solid. LCMS (ES) [M+1]⁺ m/z 396.2.

Example 33 Synthesis of10-methoxy-N-methyl-9-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-6-amineformate

The title compound was made from1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine(Intermediate III-5) and methylamine (1.0 N in THF), following aprocedure similar as described in Example 22, Step 1. The crude mixturewas filtered and subjected to purification on reverse phase preparativeHPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elutionof 5-17% MeCN in water over a 7 min period, where both solvents contain0.1% formic acid (FA)) to provide the title compound as a gray solidLCMS (ES) [M+1]⁺ m/z 385.2.

Example 34 Synthesis of10-methoxy-N-(propan-2-yl)-9-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-6-amineformate

The title compound was made from1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine(Intermediate III-5) following a procedure similar as described inExample 22, Step 1, except that propan-2-amine was used in the place ofmethyl amine. The crude mixture was filtered and subjected topurification on reverse phase preparative HPLC (Prep-C18, 5 μM XBridgecolumn, 19×150 mm, Waters; gradient elution of 5-21% MeCN in water overa 7 min period, where both solvents contain 0.1% formic acid (FA)) toprovide the title compound as a gray solid. LCMS (ES) [M+1]⁺ m/z 413.3.

Example 35 Synthesis of1-[3-({8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidineformate

To a mixture of1-[3-([4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl]oxy)propyl]pyrrolidine(Intermediate III-2) (80.00 mg; 0.21 mmol) and zinc (300 mg, 4.6 mmol,22 eq.) in MeOH was added aqueous HCl (37%, 0.5 mL). The mixture wasleft stirring at rt for 72 h and filtered through a small pad of celite.After removal of the solvents under reduced pressure, the residue wasfiltered and purified by reverse preparative HPLC (Prep-C18, 5 μM OBDcolumn, 19×250 mm, waters; gradient elution of 0-40% MeCN in water overa 20 min period, where both solvents contain 0.1% formic acid, flowrate: 20 mL/min) to provide the title compound as a brown solid. LCMS(ES) [M+1]⁺ m/z 356.2.

Example 36 Synthesis of1-[3-({4-cyclopropyl-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidineformate

A mixture of1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate III-2) (80.00 mg; 0.21 mmol; 1.00 eq.), cyclopropylboronicacid (44.06 mg; 0.51 mmol; 2.50 eq.) and K₂CO₃ (87 mg, 0.63 mmol, 3.0eq.) in a mixed solvent of N,N-dimethylformamide (2.5 mL) and water (1.0mL) in a seal vial was purged with N₂ for 10 min. To the resultingmixture was added Pd₂(dba)₃ (62 mg, 0.067 mmol, 0.32 eq.). The vial wassealed and the mixture was allowed to stir at 100° C. for 3 h. The crudereaction mixture was cooled to rt, quenched with water, and extractedwith 30% PrOH/chloroform. The organic layers were combined andconcentrated under reduced pressure. The residue was dissolved in DMSOand subjected to purification by reverse preparative HPLC (Prep-C18, 5μM OBD column, 19×250 mm, waters; gradient elution of 0-40% MeCN inwater over a 20 min period, where both solvents contain 0.1% formicacid, flow rate: 20 mL/min) to provide the title compound as a brownsolid. LCMS (ES) [M+1]⁺ m/z 396.4.

Example 37 Synthesis of8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-oltrifluoroacetate

Into a 50-mL round-bottom flask, was placed a mixture of4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2) (1.00g, 3.99 mmol, 1.00 eq.), ethyl 2-oxocyclopentane-1-carboxylate (655 mg,4.19 mmol, 1.05 eq.), p-TsOH (69 mg, 0.20 mmol, 0.05 eq.) and toluene(15 mL). The resulting mixture was allowed to stir at 110° C. for 1 h.After the starting material was consumed completely, the mixture wascooled to rt. To the mixture was added polyphosphoric acid (1 mL). Themixture was allowed to stir at 100° C. for 1.0 h. After removal ofvolatiles under reduced pressure, the residue was diluted with 100 mL ofH₂O and the pH value of the solution was adjusted to 9 with aqueous NaOHsolution (2 N). The mixture was extracted with a mixed solvent of 20%^(i)PrOH/80% CHCl₃. The combined organic layers were dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was subjected for purification on reverse preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of17-32% MeCN in water over 7 min, where both solvents contain 0.1%trifluoroacetic acid (TFA), flow rate: 20 mL/min, detector UVwavelength: 254 nm) to afford the title compound as a gray solid. LCMS(ES) [M+1]⁺ m/z 343.2.

Example 38 Synthesis of2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-oltrifluoroacetate

The title compound was made from4-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]aniline (Intermediate I-2)following a procedure similar as described in Example 37, except thatethyl 2-oxocyclohexane-1-carboxylate was used in place of ethyl2-oxocyclopentane-1-carboxylate. LCMS (ES) [M+1]⁺ m/z 375.2.

Example 39 Synthesis of2-methoxy-N-[1-(propan-2-yl)piperidin-4-yl]-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-aminetrifluoroacetate

The title compound was made from6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2) and 1-isopropylpiperidin-4-amine, following aprocedure described in Example 3, except that the crude product waspurified by reverse preparative HPLC (Prep-C18, 5 μM SunFire column,19×150 mm, Waters; gradient elution of 10-30% MeCN in water over a 7.5min period, where both solvents contain 0.1% trifluoroacetic acid (TFA))to provide the title compound as a brown solid. LCMS (ES) [M+1]⁺ m/z481.4.

Example 40 Synthesis of2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridinetrifluoroacetate

The title compound was made from6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2) following a procedure similar as described inExample 21. The crude product was purified by reverse HPLC (Prep-C18, 5μM XBridge column, 19×150 mm, Waters; gradient elution of 8-32% MeCN inwater over a 7 min period, where both solvents contain 0.1%trifluoroacetic acid (TFA)) to provide the title compounds as a lightbrown oil. LCMS (ES) [M+1]⁺ m/z 341.3.

Example 41 Synthesis ofN-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}-1-methylpiperidin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and 1-methylpiperidin-4-amine, following a proceduresimilar as described Example 3, except that the crude product waspurified by reverse preparative (Prep-C18, 5 μM OBD column, 19×250 mm,waters; gradient elution of 0-40% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) toprovide the title compound as a white solid. LCMS (ES) [M+1]⁺ m/z 439.4.

Example 42 Synthesis of2-methoxy-N-(oxan-4-yl)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amineformate

The title compound was made from6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2) and tetrahydro-2H-pyran-4-amine, following aprocedure similar as described in Example 3. The crude product waspurified by reverse preparative (Prep-C18, 5 μM OBD column, 19×250 mm,waters; gradient elution of 0-40% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) toprovide the title compound as a white solid. LCMS (ES) [M+1]⁺ m/z 440.3.

Example 43 Synthesis ofN-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}-1-(propan-2-yl)piperidin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and 1-isopropylpiperidin-4-amine following aprocedure similar as described in Example 3. The crude product waspurified by reverse preparative (Prep-C18, 5 μM OBD column, 19×250 mm,waters; gradient elution of 0-40% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) toprovide the title compound as a white solid. LCMS (ES) [M+1]⁺ m/z 467.4.

Example 44 Synthesis of8-methoxy-N-(oxetan-3-yl)-'7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and oxetan-3-amine, following a procedure similar asdescribed above in Example 3. The crude product was purified by reversepreparative (Prep-C18, 5 μM OBD column, 19×250 mm, waters; gradientelution of 5-38% MeCN in water over a 20 min period, where both solventscontain 0.1% formic acid, flow rate: 20 mL/min) to provide the titlecompound as a brown solid. LCMS (ES) [M+1]⁺ m/z 398.3.

Examples 45 and 46 Synthesis of7-methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine(45) and8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine(46)

Step 1

Into a 250-mL round-bottom flask, was placed a solution of3,4-dimethoxybenzenamine (7.5 g, 48.96 mmol, 1.00 eq.), toluene (100mL), ethyl 4-oxo-tetrahydrofuran-3-carboxylate (9.3 g, 58.75 mmol, 1.20eq.) and p-TsOH.H₂O (932 mg, 4.90 mmol, 0.1 eq.) subsequently. Theresulting mixture was allowed to stir under reflux with Dean-Stark for 4h. The resulting mixture was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate, washed with saturated aqueoussodium carbonate, brine and dried over anhydrous sodium sulfate. Afterremoval of the organic solvents under reduced pressure, the resultingbrown solid was dissolved in toluene. To the solution was added polyphosphoric acid (PPA) (20 mL). The resulting mixture was stirred at 100°C. for 4 h and then concentrated under reduced pressure. The residue wasdiluted with water and the pH value of the solution was adjusted to 7with saturated aqueous sodium bicarbonate solution. The mixture wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure to provide crude7,8-dimethoxy-1,3-dihydrofuro[3,4-c]quinolin-4-ol as a brown thick oil(7.1 g). LCMS (ES) [M+1]+ m/z 248.1.

Step 2

Into a 250-mL round-bottom flask charge with crude7,8-dimethoxy-1,3-dihydrofuro[3,4-c]quinolin-4-ol (7.1 g, crude, 28.72mmol, 1.00 eq.) was added POCl₃ (100 mL). The resulting solution wasallowed to stir at 100° C. for 4 h. After removal of volatiles underreduced pressure, the residue was treated with ice/water and the pHvalue of the solution was adjusted to 7 with aqueous NaHCO₃ (1.0 M)solution. The resulting mixture was extracted with ethyl acetate thrice.The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel eluted with ethylacetate/petroleum ether (1/2) to provide4-chloro-7,8-dimethoxy-1,3-dihydrofuro[3,4-c]quinoline as a yellow solid(3.5 g, 27%, 2 steps). LCMS (ES) [M+1]⁺ m/z 266.1.

Step 3

Into a 100-mL round-bottom flask, was placed a mixture of4-chloro-7,8-dimethoxy-1,3-dihydrofuro[3,4-c]quinoline (3.5 g, 13.17mmol, 1.00 eq.), dichloroethane (50 mL) and AlCl₃ (1.75 g, 13.17 mmol,1.0 eq.). The resulting mixture was allowed to stir at 40° C. for 6 h,cooled to rt, diluted with CH₂Cl₂ and then treated with ice water. Themixture was filtered through a pad of celite and the filter cake waswashed with CH₂Cl₂. The filtrated was concentrated under reducedpressure and the residue was purified by flash chromatography on silicagel column eluted with 5% MeOH/CH₂Cl₂ to afford a mixture of4-chloro-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinoloneand4-chloro-7-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolone(1:1) as a yellow oil (1.40 g). LCMS (ES) [M+1]⁺ m/z 252.1.

Step 4

Into a 50-mL round-bottom flask, was placed a mixture of4-chloro-8-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinoloneand4-chloro-7-methoxy-8-(3-(pyrrolidin-1-yl)propoxy)-1,3-dihydrofuro[3,4-c]quinolone(1:1, 1.40 g, 5.56 mmol, 1.00 eq.), potassium carbonate (2.30 g, 16.69mmol, 3.0 eq.), acetonitrile (30 mL), 3-(pyrrolidin-1-yl)propan-1-olhydrochloride (1.84 g, 10.01 mmol, 1.80 eq.) and potassium iodide (1.66g, 10.01 mmol, 1.80 eq.). The resulting mixture was allowed to stir at80° C. for 3 h. The solids were filtered off, and the filter cake waswashed with acetonitrile (2×30 mL). The filtrate was concentrated underreduced pressure and the resulting residue was purified by flashchromatography on silica gel column eluted with 10% MeOH/CH₂Cl₂ toprovide a mixture of1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidineand1-[3-({4-chloro-7-methoxy-1H,3H-furo[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine(1:1, 0.99 g) as a brown solid. LCMS (ES) [M+1]⁺ m/z 363.2.

Step 5

Into a 8-mL seal tube was added1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidineand1-[3-({4-chloro-7-methoxy-1H,3H-furo[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine(1:1, 330 mg, 0.91 mmol, 1.0 eq.), dry 1,4-dioxane (4 mL),propan-2-amine (269 mg, 4.56 mmol, 5.00 eq.), t-BuONa (175 mg, 1.82mmol, 2.00 eq.), 4 Å MS (50 mg) and 3rd-BrettPhos precatalyst (56 mg,0.063 mmol, 0.05 eq.) subsequently. The resulting mixture was allowed tostir at 90° C. under N₂ for 2 h. The mixture was concentrated underreduced pressure. The residue was purified by a silica gel column elutedwith 10% MeOH/CH₂Cl₂ to provide a mixture of the two crude desiredproducts (326 mg). Purification of this crude mixture bychiral-Prep-HPLC with the conditions (Phenomenex Lux Cellulose-4 column,21.2×250 mm; Mobile phase: 70% n-Hexane (0.1% diethylamine)/30% Ethanol;Flow rate: 20 mL/min; Detector 254 nm) to provide two fractions asbelow:

The first fraction was collected (Rt=6.5 min) to provide7-methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine(45) as a light yellow solid (82.5 mg). LCMS (ES) [M+1]⁺ m/z 386.3.

The second fraction was collected (Rt=7.2 min) to provide8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine(46) as a light yellow solid. LCMS (ES) [M−1]⁺ m/z 386.4.

Examples 47 and 48 Synthesis ofN-cyclopropyl-7-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine(47) andN-cyclopropyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine(48)

The title compounds were made from a mixture of1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidineand1-[3-({4-chloro-7-methoxy-1H,3H-furo[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine(1:1.) (prepared in Example 45 and 46, Step 4), following a proceduresimilar as described above in Example 45 and 46, Step 5, except thatcyclopropanamine was used in the place of propan-2-amine.

The crude mixture was purified by a silica gel column eluted with 10%MeOH/CH₂Cl₂ to provide a mixture containing both the desired products.Purification of this crude mixture by chiral-Prep-HPLC with theconditions (Phenomenex Lux Cellulose-4 column, 21.2×250 mm; Mobilephase: 70% n-Hexane (0.1% diethylamine)/30% Ethanol; Flow rate: 20mL/min; Detector 254 nm) to provide two fractions as below:

The first fraction was collected (Rt=15.0 min) to provideN-cyclopropyl-7-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine(47) as a light yellow solid (82.5 mg). LCMS (ES) [M+1]⁺ m/z 384.3.

The second fraction was collected (Rt=17.8 min) to provideN-cyclopropyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amine(48) as a light yellow solid. LCMS (ES) [M−1]⁺ m/z 384.3.

Example 49 Synthesis ofN-(cyclobutylmethyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and cyclobutylmethanamine, following a proceduresimilar as described above in Example 3. The crude product was purifiedby reverse preparative (Prep-C18, 5 μM OBD column, 19×250 mm, waters;gradient elution of 0-35% MeCN in water over a 20 min period, where bothsolvents contain 0.1% formic acid, flow rate: 20 mL/min) to provide thetitle compound as a brown solid. LCMS (ES) [M+1]⁺ m/z 410.3.

Example 50 Synthesis of9-methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]quinolin-5-amineformate

The title compound was made from1-[3-({5-chloro-9-methoxy-1H,2H,4H-pyrano[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-6) and propan-2-amine, following a procedure similaras described above in Example 3 except that reaction was conducted inmicrowave reactor at 80° C. for 3 h. The crude product was purified byreverse preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm,Waters; gradient elution of 13-35% MeCN in water over a 7 min period,where both solvents contain 0.1% formic acid) to provide the titlecompound as a yellow solid. LCMS (ES) [M+1]⁺ m/z 400.3.

Example 51 Synthesis of2-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]-N-(propan-2-yl)-7,8,9,10-tetrahydrophenanthridin-6-amineformate

The title compound was made from6-chloro-2-methoxy-3-[(1-methylpyrrolidin-3-yl)methoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-6) and propan-2-amine, following a procedure similar asdescribed above in Example 3. The crude product was purified by reversepreparative HPLC (Prep-C18, 5 μM SunFire column, 19×150 mm, Waters;gradient elution of 17-34% MeCN in water over a 7 min period, where bothsolvents contain 0.1% FA) to provide the title compound as a dark greensolid. LCMS (ES) [M+1]⁺ m/z 384.3.

Example 52 Synthesis of9-methoxy-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]benzo[h]1,6-naphthyridin-5-amineformate

The title compound was made from1-[3-({5-chloro-9-methoxybenzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-3) and propan-2-amine, following a procedure similaras described above in Example 3. The crude product was purified byreverse preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm,Waters; gradient elution of 8-24% MeCN in water over a 7 min period,where both solvents contain 0.1% FA) to provide the title compound as abrown solid. LCMS (ES) [M+1]⁺ m/z 395.3.

Example 53 Synthesis of8-methoxy-N,2,2-trimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-4) and ethylamine (2.0 M in THF), following a proceduresimilar as described above in Example 3. The crude product was purifiedby reverse preparative HPLC ((Prep-C18, 5 μM OBD column, 19×250 mm,waters; gradient elution of 0-40% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) toprovide the title compound as a brown solid. LCMS (ES) [M+1]⁺ m/z 384.3.

Example 54 Synthesis of8-methoxy-2,2-dimethyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-4) and propan-2-amine, following a procedure similar asdescribed above in Example 3. The crude product was purified by reversepreparative HPLC ((Prep-C18, 5 μM OBD column, 19×250 mm, waters;gradient elution of 0-40% MeCN in water over a 20 min period, where bothsolvents contain 0.1% formic acid, flow rate: 20 mL/min) to provide thetitle compound as a brown solid. LCMS (ES) [M+1]⁺ m/z 412.3.

Example 55 Synthesis ofN-cyclopropyl-9-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]-quinolin-5-amineformate

The title compound was made from1-[3-({5-chloro-9-methoxy-1H,2H,4H-pyrano[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-6) and cyclopropanamine, following a procedure similaras described above in Example 3, except that reaction was conducted inmicrowave reactor at 80° C. for 3 h. The crude product was purified byreverse preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm,Waters; gradient elution of 13-35% MeCN in water over a 7 min period,where both solvents contain 0.1% formic acid) to provide the titlecompound as a yellow solid. LCMS (ES) [M+1]⁺ m/z 398.2.

Example 56 Synthesis of9-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]pyrazolo[1,5-c]quinazolin-5-olformate

Step 1

A mixture of 1H-pyrazol-5-ylboronic acid (186.90 mg; 1.67 mmol; 1.20eq.), potassium carbonate (384.17 mg; 2.78 mmol; 2.00 eq.) and1-[3-(4-bromo-2-methoxy-5-nitrophenoxy)-propyl]pyrrolidine (500.00 mg;1.39 mmol; 1.00 eq.) in a mixed solvent of dimethylethane (2.0 mL) andwater (0.6 mL) in a seal vial was purged with N₂ for 10 min. To themixture was added Pd(PPh₃)₄ (80 mg, 0.07 mmol, 0.05 eq.) and CuI (27 mg,0.14 mmol, 0.10 eq.). The vial was sealed and the mixture was allowed tostir at 100° C. for 16 h. The crude reaction mixture was cooled to rt,quenched with water, extracted with 30%^(i)PrOH/chloroform. The organiclayers were combined and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel column elutedwith 5-15% solvent A in CH₂Cl₂ (Solvent A is 0.1% NH₄OH/10% MeOH/CH₂Cl₂)to provide5-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-1H-pyrazoleas a brown syrup (310 mg, 64%). LCMS (ES) [M+1]⁺ m/z 347.3.

Step 2

To a solution of5-{5-methoxy-2-nitro-4-[3-(pyrrolidin-1-yl)propoxy]phenyl}-1H-pyrazole(310.00 mg; 0.89 mol) in MeOH (8 mL) was added Pd/C (30 mg). Thereaction flask was purged with nitrogen once followed with hydrogentwice. The mixture was allowed to stir at 60° C. for 2.5 h. The solidwas filtered off through a small pad of celite. Removal of the organicsolvent under reduced pressure provided4-methoxy-2-(1H-pyrazol-5-yl)-5-[3-(pyrrolidin-1-yl)propoxy]aniline as abrown oil (252 mg, 92%). LCMS (ES) [M+1]⁺ m/z 317.3.

Step 3

To a flask charged with4-methoxy-2-(1H-pyrazol-5-yl)-5-[3-(pyrrolidin-1-yl)propoxy]aniline(152.00 mg; 0.48 mmol; 1.00 eq.) was added anhydrous CH₂Cl₂ (4 mL)followed by N,N-diisopropylethylamine (0.2 mL). The resulting solutionwas cooled to −78° C. and to the mixture was added bis(trichloromethyl)carbonate (49.90 mg; 0.17 mmol; 0.35 eq.). After stirring at −78° C. for20 min, the reaction flask was removed from the bath and allowed to stirat rt for 2 h. The reaction mixture was quenched with water andextracted with 30%^(i)PrOH/chloroform thrice. The organic layers werecombined and concentrated under reduced pressure. The residue wasdissolve din DMSO and subjected to purification by reverse preparativeHPLC (Prep-C18, 5 μM OBD column, 19×250 mm, waters; gradient elution of0-40% MeCN in water over a 20 min period, where both solvents contain0.1% formic acid, flow rate: 20 mL/min) to provide the title compound asa white solid (33 mg, 19%). LCMS (ES) [M+1]⁺ m/z 343.3.

Example 57 Synthesis of9-methoxy-N-methyl-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]quinolin-5-amineformate

The title compound was made from1-[3-({5-chloro-9-methoxy-1H,2H,4H-pyrano[3,4-c]-quinolin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-6) and methyl amine (2.0 M in THF), following aprocedure similar as described above in Example 3, except that reactionwas conducted in microwave reactor at 120° C. for 1.0 h. The crudeproduct was purified by reverse preparative HPLC (Prep-C18, 5 mM XBridgecolumn, 19×150 mm, Waters; gradient elution of 13-35% MeCN in water overa 7 min period, where both solvents contain 0.1% formic acid) to providethe title compound as a yellow solid. LCMS (ES) [M+1]⁺ m/z 372.2.

Example 58 Synthesis ofN-ethyl-9-methoxy-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,4H-pyrano[3,4-c]quinolin-5-amineformate

The title compound was made from1-[3-({5-chloro-9-methoxy-1H,2H,4H-pyrano[3,4-c]quinolin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-6) and ethylamine (2.0 M in THF), following aprocedure similar as described above in Example 3, except that thereaction was conducted in microwave reactor at 120° C. for 1.0 h. Thecrude product was purified by reverse preparative HPLC (Prep-C18, 5 mMXBridge column, 19×150 mm, Waters; gradient elution of 13-35% MeCN inwater over a 7 min period, where both solvents contain 0.1% formic acid)to provide the title compound as a yellow solid. LCMS (ES) [M+1]⁺ m/z386.2.

Example 59 Synthesis of8-methoxy-N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate III-7) and methylamine (2.0 N in THF), following aprocedure similar as described above in Example 3, except that thereaction was conducted in microwave reactor at 100° C. for 1.0 h. Thecrude product was purified by reverse preparative HPLC (Prep-C18, 5 μMXBridge column, 19×150 mm, Waters; gradient elution of 13-35% MeCN inwater over a 7 min period, where both solvents contain 0.1% formic acid)to provide the title compound as a light brown solid. ¹H NMR (300 MHz,CD₃OD-d₆, ppm): 8.48 (br, 1H), 7.38 (s, 1H), 6.92 (s, 1H), 5.34 (s, 2H),5.05 (s, 2H), 4.31-4.28 (m, 2H), 3.93 (s, 3H), 3.61-3.47 (m, 6H), 3.10(s, 3H), 2.38-2.36 (m, 2H), 2.15-2.10 (m, 4H). LCMS (ES) [M+1]⁺ m/z358.2.

Example 60 Synthesis ofN-ethyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,3H-furo[3,4-c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,3H-furo[3,4-c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate III-7) and ethylamine (2.0 N in THF), following aprocedure similar as described above in Example 3, except that thereaction was conducted in microwave reactor at 100° C. for 1.0 h. Thecrude product was purified by reverse preparative HPLC (Prep-C18, 5 μMXBridge column, 19×150 mm, Waters; gradient elution of 13-35% MeCN inwater over a 7 min period, where both solvents contain 0.1% formic acid)to provide the title compound as a light brown solid. LCMS (ES) [M+1]⁺m/z 372.2.

Example 61 Synthesis of2-methoxy-6-(methylamino)-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-8-olformate

Step 1

Into a 40-mL seal tube vial purged and maintained with an inertatmosphere of nitrogen, was placed a mixture of8-(benzyloxy)-6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate III-8) (1.00 g, 2.08 mmol, 1.00 eq.), anhydrous1,4-dioxane (10 mL), MeNH₂ (5.2 mL, 2 N in THF, 10.4 mmol, 5.00 eq.),3rd Brettphos precatalyst (189 mg, 0.208 mmol, 0.10 eq.), t-BuONa (400mg, 4.16 mmol, 2.00 eq.) and 4 Å MS (400 mg) subsequently. The vial wassealed and the resulting solution was allowed to stir for 16 h at 90° C.under nitrogen atmosphere. The mixture was cooled to rt, diluted with100 mL of 10% MeOH/CH₂Cl₂, filtered through a pad of celite. Thefiltrate was concentrated under reduced pressure to provide a crudeproduct of8-(benzyloxy)-2-methoxy-N-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amineas a brown crude oil (956 mg). LCMS (ES) [M+1]⁺ m/z 476.4.

Step 2

Into a 0° C. solution of8-(benzyloxy)-2-methoxy-N-methyl-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-amine(500 mg, 1.05 mmol, 1.00 eq.) in CH₂Cl₂ (8 mL) was added TMSI (421 mg,2.10 mmol, 2.00 eq.) dropwise with stirring. The resulting mixture wasallowed to stir at room temperature for 4 h. The reaction mixture wasthen quenched by saturated aq. NaHCO₃. The mixture was diluted with 10%MeOH/CH₂Cl₂, dried over anhydrous sodium sulfate, filtered through a padof celite. The filtrate was concentrated under reduced pressure. Theresidue was diluted with 5 mL of N,N-dimethylformamide, filtered andsubjected to reverse phase preparative HPLC (Prep-C18, 5 μM SunFirecolumn, 19×150 mm, Waters; gradient elution of 18%-22% MeCN in waterover a 8 min period, where both solvents contain 0.05% FA) to providethe title compound as a green solid. LCMS (ES) [M+1]⁺ m/z 386.2.

Example 62 Synthesis of1-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclopropane-1-carboxylicacid formate

A mixture of1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]-pyrrolidine(Intermediate II-1) (150 mg, 0.42 mmol, 1.00 eq.), 1,4-dioxane (5 mL),and t-BuONa (160 mg, 1.66 mmol, 4.00 eq.) in a microwave reaction vialwas purged with N₂ for 5 min. To the solution was added1-aminocyclopropane-1-carbonitrile hydrochloride (103 mg, 0.86 mol, 2.1eq.), and 3rd Generation BrettPhos pre-catalyst (32 mg, 0.04 mmol, 0.05eq.). After being purged with N₂ for additional 2 min, the resultingsolution was sealed and subjected to microwave reactor (130° C., 2.5 h).The reaction mixture was allowed to cool to rt and quenched with H₂O.The resulting mixture was allowed to stir at rt for 2 h. After removalof the volatiles under reduced pressure, the residue was re-dissolved inDMSO, filtered and subjected to reverse preparative HPLC (Prep-C18, 5 μMOBD column, 19×250 mm, waters; gradient elution of 0-40% MeCN in waterover a 20 min period, where both solvents contain 0.1% formic acid, flowrate: 20 mL/min)) to provide the title compound as a brown oil (65 mg,38%). LCMS (ES) [M+1]⁺ m/z 426.2.

Example 63 Synthesis of6-fluoro-8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-6-fluoro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-7) and propan-2-amine, following a procedure similar asdescribed above in Example 3. The crude product was purified by reversepreparative HPLC (Prep-C18, 5 mM XBridge column, 19×150 mm, Waters;gradient elution of 13-35% MeCN in water over a 7 min period, where bothsolvents contain 0.1% formic acid) to provide the title compound as alight brown oil. LCMS (ES) [M+1]⁺ m/z 402.2.

Example 64 Synthesis of3-({2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-6-yl}amino)cyclobutan-1-olformate

The title compound was made from6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2) and trans-3-aminocyclobutane-1-ol, following asprocedure similar as described above in Example 3. The crude product waspurified by reverse preparative HPLC (Prep-C18, 5 μM XBridge column,19×150 mm, Waters; gradient elution of 10-28% MeCN in water over a 7 minperiod, where both solvents contain 0.1% formic acid (FA)) to providethe title compound as a yellow solid. LCMS (ES) [M+1]⁺ m/z 426.3.

Example 65 Synthesis of8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-N-(2,2,2-trifluoroethyl)-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and 2,2,2-trifluoroethan-1-amine, following aprocedure similar as described above in Example 3. The crude mixture wasfiltered and subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of10-25% MeCN in water over a 7 min period, where both solvents contain0.1% formic acid (FA)) to provide the title compound as an off-whitesolid. LCMS (ES) [M+1]⁺ m/z 424.3.

Example 66 Synthesis of8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-N-(3,3,3-trifluoropropyl)-1H,2H,3H-cyclopenta[c]quinolin-4-amine

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and 3,3,3-trifluoropropan-1-amine, following zprocedure similar as described above in Example 3, except that the crudemixture was filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel column elutedwith 10% MeOH/CH₂Cl₂ to provide the title compound as a yellow solid.LC-MS (ES) [M+1]⁺ m/z: 438.2.

Example 67 Synthesis of2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-N-(2,2,2-trifluoroethyl)-7,8,9,10-tetrahydrophenanthridin-6-amineformate

The title compound was made from6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate II-2) and 2,2,2-trifluoroethan-1-amine, following aprocedure similar described above in Example 3, except that the crudemixture was filtered and subjected to purification on reverse phasepreparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters;gradient elution of 12-27% MeCN in water over a 7 min period, where bothsolvents contain 0.1% formic acid (FA)) to provide the title compound asan off-white solid (116.3 mg, 36%). LCMS (ES) [M+1]⁺ m/z 438.4.

Example 68 Synthesis of2-methoxy-6-[(propan-2-yl)amino]-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridin-8-oltrifluoroacetate

The title compound was made from8-(benzyloxy)-6-chloro-2-methoxy-3-[3-(pyrrolidin-1-yl)propoxy]-7,8,9,10-tetrahydrophenanthridine(Intermediate III-8) following a procedure similar as described above inExample 61, except that propan-2-amine was used in place of MeNH₂. Thecrude product of the final step as purified by reverse preparative HPLC(Prep-C18, 5 μM SunFire column, 19×150 mm, Waters; gradient elution of8-22% MeCN in water over a 8 min period, where both solvents contain0.1% trifluoroacetic acid (TFA)) to provide the title compound as alight brown oil (90.0 mg, 18% over 2 steps). ⁻LCMS (ES) [M+1]⁺ m/z414.2.

Example 69 Synthesis of8-methoxy-N-methyl-N-phenyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and N-methylaniline following a procedure similar asdescribed above in Example 5, except that reaction solution was allowedto stir at 100° C. under N₂ atmosphere for 16 h. The crude mixture wasfiltered and subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM SunFire column, 19×150 mm, Waters; gradient elution of5-20% MeCN in water over a 1 min period and 20-35% MeCN in water over a9 min period, where both solvents contain 0.1% trifluoroacetic acid(TFA)) to provide the title compound as a yellow solid. ⁻LCMS (ES)[M+1]⁺ m/z 432.2.

Example 70 Synthesis of1-{8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}pyrrolidineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and pyrrolidine, following a procedure similar asdescribed above in Example 5, except that reaction solution was allowedto stir at 100° C. under N₂ atmosphere for 16 h. The crude reactionmixture was filtered and subjected to purification on reverse phasepreparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters;gradient elution of 5-22% MeCN in water over a 7 min period, where bothsolvents contain 0.1% formic acid (FA)) to provide the title compound asa dark green solid. LCMS (ES) [M+1]⁺ m/z 396.2.

Example 71 Synthesis of9-methoxy-3-methyl-N-(propan-2-yl)-8-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H,4H-benzo[c]2,7-naphthyridin-5-amineformate

Into a 8-mL seal vial, was placed a mixture of1-[3-({5-chloro-9-methoxy-3-methyl-1H,2H,3H,4H-benzo[c]2,7-naphthyridin-8-yl}oxy)propyl]pyrrolidine(Intermediate III-9) (110 mg, 0.281 mmol, 1.00 eq.), dry 1.4-dioxane (3mL), propan-2-amine (83 mg, 1.40 mmol, 5.00 eq.), t-BuONa (81 mg, 0.843mmol, 3.00 eq.) and 3rd-BrettPhos precatalyst (12 mg, 0.013 mmol, 0.05eq.) subsequently. The resulting mixture was allowed to stir at 100° C.under N₂ for 1 h. The mixture was concentrated under reduced pressureand the resulting residue was dissolved in N,N-dimethylformamide (5 mL)and subjected to reverse preparative HPLC (Prep-C18, 5 mM XBridgecolumn, 19×150 mm, Waters; gradient elution of 13-35% MeCN in water overa 7 min period, where both solvents contain 0.1% formic acid) to providethe title compound as a brown solid (72 mg, 62%). LCMS (ES) [M+1]⁺ m/z413.3.

Example 72 Synthesis of8-methoxy-N-methyl-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

Into a 50-mL sealed tube was placed8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine(Example 3) (110 mg, 0.29 mmol, 1.00 eq.), ethanol (10 mL), CH₂O (aq.37%) (0.23 mL, 2.90 mmol, 10.00 eq.) and NaBH₃CN (54 mg, 0.86 mmol, 3.00eq.) subsequently. The resulting solution was allowed to stir at 120° C.for 16 h. The crude reaction mixture was filtered and subjected topurification on reverse phase preparative HPLC (Prep-C18, 5 μM SunFirecolumn, 19×150 mm, Waters; gradient elution of 20-32% MeCN in water overa 9.5 min period, where both solvents contain 0.1% trifluoroacetic acid(TFA)) to provide the title compound as a yellow solid. LCMS (ES) [M+1]⁺m/z 398.3.

Example 73 Synthesis ofN-cyclopentyl-8-methoxy-N-methyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

The title compound was made fromN-cyclopentyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine(Example 8) following a procedure similar as described above in Example72, except that the reaction solution was allowed to stir at 120° C. for2 days. The crude reaction mixture was filtered and subjected topurification on reverse phase preparative HPLC (Prep-C18, 5 μM SunFirecolumn, 19×150 mm, Waters; gradient elution of 20-42% MeCN in water overa 9.5 min period, where both solvents contain 0.1% trifluoroacetic acid(TFA)) to provide the title compound as a yellow semi-solid. LCMS (ES)[M+1]⁺ m/z 424.3.

Example 74 Synthesis ofN-ethyl-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-4) and ethylamine (2.0 M in THF), following a proceduresimilar as described above in Example 3, The crude product was purifiedby reverse preparative HPLC ((Prep-C18, 5 μM OBD column, 19×250 mm,waters; gradient elution of 0-40% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) toprovide the title compound as a brown solid. LCMS (ES) [M+1]⁺ m/z 398.3.

Example 75 Synthesis of1-[3-({9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidineformate

To a 8-mL vial was added dioxane/H₂O (4 mL, V/V=5/1),1-[3-([5-chloro-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine(Intermediate III-10) (200 mg, 0.50 mmol, 1.00 eq.), K₃PO₄ (212 mg, 1.00mmol, 2.00 eq.) and Pd(Amphos)Cl₂ (35 mg, 0.05 mmol, 0.10 eq.). Theresulting mixture was stirred for 16 h at 90° C. under N₂. The mixturewas concentrated under vacuum. To the residue was added DMF (5 mL). Themixture was filtered and subjected to reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of5% MeCN in water to 15% MeCN in water over a 6 min period, where bothsolvents contain 0.1% formic acid) to provide the title compound (7.9mg, 4%) as a brown semi-solid. ¹H NMR (300 MHz, CD₃OD-d₄): δ 8.10 (s,1H), 7.78 (s, 1H), 7.23 (s, 1H), 4.34 (br, 2H), 4.06 (s, 3H), 3.56-3.48(m, 6H), 2.96 (t, J=6.3 Hz, 2H), 2.38 (br, 2H), 2.15 (br, 4H), 1.91 (t,J=6.3 Hz, 2H), 1.49 (s, 6H). LCMS (ES) [M+1]⁺ m/z 370.2.

Example 76 Synthesis of1-[3-({5-cyclopropyl-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidineformate

Into a 40-mL vial, was placed a mixture of1-[3-([5-chloro-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine(Intermediate III-10) (700 mg, 1.73 mmol, 1.00 eq.), toluene (20 mL),water (2 mL), cyclopropylboronic acid (1.09 g, 12.69 mmol, 5.00 eq.),Pd(dppf)Cl₂ (115 mg, 0.16 mmol, 0.10 eq.) and potassium carbonate (1.09g, 7.89 mmol, 5.00 eq.). The resulting mixture was stirred for 2 h at90° C. under N₂ and then concentrated under vacuum. The residue wasdiluted with DMF (5 mL), filtered and subjected to reverse preparativeHPLC (Prep-C18, 20-45 μM, 120 g, Tianjin Bonna-Agela Technologies;gradient elution of 5% MeCN in water to 30% MeCN in water over a 10 minperiod, where both solvents contain 0.1% formic acid) to provide thetitle compound (59.8 mg, 6%) as a brown semi-solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.23 (s, 3H), 7.45 (s, 1H), 7.08 (s, 1H), 6.86 (s, 1H), 4.10(t, J=6.3 Hz, 2H), 3.90 (s, 3H), 2.90 (t, J=6.3 Hz, 2H), 2.76-2.67 (m,6H), 2.21-2.13 (m, 1H), 2.08-1.96 (m, 2H), 1.77-1.75 (m, 6H), 1.31 (s,6H), 1.05-0.88 (m, 4H). LCMS (ES) [M+1]⁺ m/z 410.5.

Example 77 Synthesis of1-(3-{[9-methoxy-2,2-dimethyl-5-(propan-2-yl)-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl]oxy}propyl)pyrrolidineformate

Step 1

Into a 40-mL vial, was placed a mixture of1-[3-([5-chloro-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine(Intermediate III-10) (700 mg, 1.74 mmol, 1.00 eq.), ethylene glycoldimethyl ether (20 mL), water (2 mL),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.46 g, 8.70mmol, 5.00 eq.), Pd(PPh₃)₄ (402 mg, 0.348 mmol, 0.20 eq.) and Cs₂CO₃(2.83 g, 8.70 mmol, 5.00 eq.). The resulting mixture was stirred for 2 hat 90° C. under N₂. The reaction mixture was cooled to rt andconcentrated under vacuum. The residue was diluted with DMF (5 mL),filtered and subjected to reverse preparative HPLC (Prep-C18, 20-45 μM,120 g, Tianjin Bonna-Agela Technologies; gradient elution of 5% MeCN inwater to 30% MeCN in water over a 10 min period, where both solventscontain 0.1% formic acid) to provide9-methoxy-2,2-dimethyl-5-(prop-1-en-2-yl)-8-(3-(pyrrolidin-1-yl)propoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine(316.0 mg, 45%) as a brown oil. LCMS (ES) [M+1]⁺ m/z 410.5.

Step 2

Into a 25-mL round-bottom flask, was placed a mixture of1-(3-[[9-methoxy-2,2-dimethyl-5-(prop-1-en-2-yl)-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl]oxy]propyl)pyrrolidine(316 mg, 0.77 mmol, 1.00 eq.), methanol (10 mL) and 10% Pd/C (300 mg).The mixture was degassed and purged with hydrogen for 3 times. Theresulting mixture was stirred for 1 h under H₂ at room temperature. Themixture was filtered, and the filtrate was subjected to reversepreparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters;gradient elution of 9% MeCN in water to 18% MeCN in water over a 6 minperiod, where both solvents contain 0.1% formic acid) to provide thetitle compound (17.2 mg, 13%) as a yellow semi-solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.27 (s, 3H), 7.54 (s, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 4.14(t, J=6.3 Hz, 2H), 3.92 (s, 3H), 3.40-3.31 (m, 1H), 2.82-2.67 (m, 8H),2.08-2.01 (m, 2H), 1.76-1.74 (m, 6H), 1.33 (s, 6H), 1.28 (d, J=6.6 Hz,6H). LCMS (ES) [M+1]⁺ m/z 412.5.

Example 78 Synthesis of1-[3-({9-methoxy-2,2,5-trimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl}oxy)propyl]pyrrolidine

Into a 40-mL vial, was placed a mixture of1-[3-([5-chloro-9-methoxy-2,2-dimethyl-1H,2H,3H,4H-benzo[h]1,6-naphthyridin-8-yl]oxy)propyl]pyrrolidine(Intermediate III-10) (700 mg, 1.73 mmol, 1.00 eq.), dioxane (20 mL),water (2 mL), methylboronic acid (1.5 g, 25.06 mmol, 10.00 eq.),Pd(PPh₃)₄ (402 mg, 0.35 mmol, 0.20 eq.) and potassium carbonate (1.02 g,7.38 mmol, 5.00 eq.). The resulting mixture was stirred for 2 h at 90°C. under N₂. The crude reaction mixture was filtered and subjected toreverse preparative HPLC (Prep-C18, 20-45 μM, 120 g, Tianjin Bonna-AgelaTechnologies; gradient elution of 5% MeCN in water to 25% MeCN in waterover a 8 min period, where both solvents contain 0.1% formic acid) toprovide the title compound as a brown semi-solid (114.6, 13%). ¹H NMR(300 MHz, DMSO-d₆) δ 8.29 (s, 3H), 7.75 (s, 1H), 7.63 (s, 1H), 7.31 (s,1H), 4.13 (t, J=6.0 Hz, 2H), 3.93 (s, 3H), 2.74-2.67 (m, 4H), 2.66-2.61(m, 4H), 2.50 (s, 3H), 2.08-1.95 (m, 2H), 1.78-1.74 (m, 6H), 1.35 (s,6H). LCMS (ES) [M+1]⁺ m/z 384.4

Example 79 Synthesis of1-[3-({6-cyclopentyl-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidinetriflate

The title compound was made from1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine(Intermediate III-5) and2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,following a procedure similar as described above in Example 77 above,except that reaction solution was allowed to stir at 100° C. under N₂atmosphere for 16 h. The crude was purified by reverse phase preparativeHPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elutionof 17% MeCN in water to 32% MeCN in water over a 6 min period, whereboth solvents contain 0.05% TFA) to provide the title compound as abrown viscous oil (88.4 mg, 24%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.23 (br,1H), 9.69 (br, 1H), 8.48 (br, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 4.21-4.17(m, 2H), 3.92 (s, 3H), 3.77-3.71 (m, 2H), 3.68-3.58 (m, 2H), 3.56-3.47(m, 1H), 3.41-3.29 (m, 2H), 3.13-2.97 (m, 4H), 2.29-2.21 (m, 2H),2.10-1.70 (m, 16H). LCMS (ES) [M+1]⁺ m/z 424.3.

Example 80 Synthesis of1-[3-({6-cyclopropyl-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidinetrifluoroacetate

Into a 40-mL vial, was placed a mixture of1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine(Intermediate III-5) (500 mg, 1.28 mmol, 1.00 eq.), toluene (10 mL),cyclopropylboronic acid (222 mg, 2.58 mmol, 2.00 eq.), potassiumcarbonate (534 mg, 3.86 mmol, 3.00 eq.) and Pd(dppf)Cl₂ (98.2 mg, 0.13mmol, 0.10 eq.). The resulting mixture was stirred for 16 h at 100° C.under N₂ and then concentrated under vacuum. The residue was dissolvedin DMF (5 mL), filtered and subjected to reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of2% MeCN in water to 25% MeCN in water over a 6 min period, where bothsolvents contain 0.05% TFA) to provide the title compound as a yellowoil (111.1 mg, 14%). ¹HNMR (300 MHz, DMSO-d₆) δ 12.33 (s, 1H), 9.67 (br,1H), 8.44 (br, 1H), 7.64 (s, 1H), 7.43 (s, 1H), 4.18-4.15 (m, 2H), 3.92(s, 3H), 3.77-3.71 (m, 2H), 3.69-3.61 (m, 2H), 3.36-3.28 (m, 2H),3.22-3.17 (m, 2H), 3.13-2.99 (m, 2H), 2.31-2.23 (m, 3H), 2.13-1.98 (m,6H), 1.89-1.80 (m, 2H), 1.18-1.13 (m, 2H), 1.06-1.00 (m, 2H). LCMS (ES)[M+1]⁺ m/z 396.3.

Example 81 Synthesis of1-(3-{[10-methoxy-6-(propan-2-yl)-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl]oxy}propyl)pyrrolidinetrifluoroacetate

The title compound was made from1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine(Intermediate III-5) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane, following aprocedure similar as described above in Example 79 above, except thatreaction solvents were DME/H₂O (V/V=5/1) and allowed to stir at 100° C.under N₂ atmosphere for 16 h. The crude product was purified by reversephase preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm,Waters; gradient elution of 16% MeCN in water to 30% MeCN in water overa 6 min period, where both solvents contain 0.05% TFA) to provide thetitle compound as a yellow solid (101.4 mg, 40%). ¹H NMR (300 MHz,DMSO-d₆) δ 12.35 (br, 1H), 9.86 (br, 1H), 8.53 (br, 1H), 7.66 (s, 1H),7.55 (s, 1H), 4.21-4.18 (m, 2H), 3.92 (s, 3H), 3.77-3.71 (m, 2H),3.68-3.59 (m, 2H), 3.53-3.45 (m, 1H), 3.37-3.30 (m, 2H), 3.12-2.97 (m,4H), 2.29-2.21 (m, 2H), 2.04-1.82 (m, 8H), 1.36 (d, J=6.9 Hz, 6H). LCMS(ES) [M+1]⁺ m/z 398.2.

Example 82 Synthesis of1-[3-({10-methoxy-6-methyl-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidinetrifluoroacetate

Into a 40-mL vial, was placed a mixture of1-[3-({6-chloro-10-methoxy-1H,2H,3H,4H,5H-azepino[3,2-c]quinolin-9-yl}oxy)propyl]pyrrolidine(Intermediate III-5) (500 mg, 1.28 mmol, 1.00 eq.), dioxane (5 mL),methylboronic acid (93 mg, 1.55 mmol, 1.20 eq.), Pd(PPh₃)₄ (68 mg, 0.064mmol, 0.05 eq.) and potassium carbonate (534 mg, 3.86 mmol, 3.00 eq.).The mixture was stirred for 16 h at 100° C. under N₂ and thenconcentrated under vacuum. The residue was diluted with DMF (10 mL),filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μMX Bridge column, 19×150 mm, Waters; gradient elution of 17% MeCN inwater to 32% MeCN in water over a 6 min period, where both solventscontain 0.05% trifluoroacetic acid) to provide the title compound as ayellow oil (114.3 mg, 18%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.76 (br, 1H),8.42 (br, 1H), 7.66 (s, 1H), 7.23 (s, 1H), 4.19 (t, J=5.7 Hz, 2H), 3.92(s, 3H), 3.75-3.70 (m, 2H), 3.68-3.63 (m, 2H), 3.36-3.29 (m, 2H),3.10-3.00 (m, 2H), 2.97-2.94 (m, 2H), 2.55 (s, 3H), 2.27-2.20 (m, 2H),2.12-1.92 (m, 6H), 1.91-1.88 (m, 2H). LCMS (ES) [M+1]⁺ m/z 370.2.

Example 83 Synthesis of1-(3-{[4-(cyclopent-1-en-1-yl)-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl]oxy}propyl)pyrrolidine

Into a 8 mL seal tube under N₂ was added a mixture of1-[3-[4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl]oxy)propyl]pyrrolidine(Intermediate III-2) (250.00 mg; 0.64 mmol; 1.00 eq.),1-cyclopenten-1-ylboronic acid (143.54 mg; 1.28 mmol; 2.00 eq.),4-[di(tert-butyl)phosphino]-N,N-dimethylaniline compound withdichloropalladium (2:1) (90.80 mg; 0.13 mmol; 0.20 eq.) and K₃PO₄(680.48 mg; 3.21 mmol; 5.00 eq.) in toluene (7.50 mL) and water (0.75mL). The vial was sealed and heated at 60° C. for 90 min. The volatileswere removed under reduced pressure and the residue was redissolved inDMSO, filtered and subjected to purification on reverse phasepreparative HPLC (Prep-C18 XSelect, 5 μM column, 19×150 mm, Waters;gradient elution of 0-50% MeCN in water over a 20 min period, where bothsolvents contain 0.1% hydrochloric acid) to provide the title compound(110 mg, 32%). LCMS (ES) [M+1]⁺ m/z 422.1.

Example 84 Synthesis of4-[(propan-2-yl)amino]-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-8-oltrifluoroacetate

Into a 100-mL round-bottom flask, was placed a solution of8-methoxy-N-(propan-2-yl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amine(1.0 g, 2.61 mmol, 1.00 eq.), AcOH (20 mL) and 48% HBr aqueous solution(20 mL). The resulting solution was stirred for 16 h at 100° C. and thenconcentrated under vacuum. The residue was diluted with DMF (20 mL),filtered and subjected to reverse phase preparative MPLC (Prep-C18,20-45 μM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of10% MeCN in water to 25% MeCN in water over a 10 min period, where bothsolvents contain 0.05% TFA) to provide the title compound as a brownsolid (750 mg, 48%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.38 (s, 1H), 9.90(br, 2H), 8.12 (d, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.11 (s, 1H), 4.37-4.28(m, 1H), 4.18 (t, J=5.4 Hz, 2H), 3.71-3.57 (m, 2H), 3.47-3.33 (m, 2H),3.21-3.00 (m, 4H), 2.92-2.86 (m, 2H), 2.23-2.10 (m, 4H), 2.07-2.00 (m,2H), 1.99-1.81 (m, 2H), 1.33 (d, J=6.3 Hz, 6H). LCMS (ES) [M+1]⁺ m/z370.3.

Example 85 Synthesis of8-methoxy-7-[3-(piperidin-1-yl)propoxy]-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from4-chloro-8-methoxy-7-(3-(piperidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolone(Intermediate III-11) and propan-2-amine, following a procedure similaras described above in Example 5. The crude reaction mixture was filteredand subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM, X Bridge column, 19×150 mm, Waters; gradient elution of7% MeCN in water to 27% MeCN in water over a 6 min period, where bothsolvents contain 0.1% formic acid) to provide the title compound as ayellow solid (197.7 mg, 38%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.25 (s, 2H),7.02 (s, 1H), 6.93 (s, 1H), 5.74 (d, J=7.5 Hz, 1H), 4.44-4.34 (m, 1H),4.09 (t, J=6.0 Hz, 2H), 3.82 (s, 3H), 3.05 (t, J=7.2 Hz, 2H), 2.83-2.75(m, 8H), 2.20-2.02 (m, 4H), 1.65-1.60 (m, 4H), 1.52-1.47 (m, 2H), 1.21(d, J=6.9 Hz, 6H). LCMS (ES) [M+1]⁺ m/z 398.3.

Example 86 Synthesis of7-[3-(3,3-dimethylpyrrolidin-1-yl)propoxy]-8-methoxy-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from 1-[3-([4-chloro-8-methoxy-1H, 2H,3H-cyclopenta[c]quinolin-7-yl]oxy) propyl]-3, 3-dimethylpyrrolidine(Intermediate III-12) and propan-2-amine, following a procedure similaras described above in Example 5. The crude reaction mixture was filteredand subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of5% MeCN in water to 21% MeCN in water over a 6 min period, where bothsolvents contain 0.1% formic acid) to provide the title compound as ayellow solid (103.1 mg, 20%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (s, 2H),7.01 (s, 1H), 6.93 (s, 1H), 5.72 (d, J=8.1 Hz, 1H), 4.47-4.30 (m, 1H),4.10 (t, J=6.3 Hz, 2H), 3.82 (s, 3H), 3.05 (t, J=7.2 Hz, 2H), 2.87-2.81(m, 2H), 2.79-2.74 (m, 4H), 2.55-2.51 (m, 2H), 2.19-2.05 (m, 2H),2.00-1.95 (m, 2H), 1.61 (t, J=7.2 Hz, 2H), 1.21 (d, J=6.3 Hz, 6H), 1.08(s, 6H). LCMS (ES) m/z 412.3 [M−1]⁺.

Example 87 Synthesis of8-methoxy-2,2-dimethyl-N-(3-methylbutyl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-4) and 3-methyl butanamine, following a proceduresimilar as described in Example 3 above. The reaction mixture wasfiltered and concentrated and the crude dissolved in dimethylsulfoxideand subjected to purification on reverse phase preparative HPLC(Prep-C18 XSelect, 5 μM column, 19×150 mm, Waters; gradient elution of19-35% MeCN in water over a 7 min period, where both solvents contain0.1% formic acid) to provide the title compound as a white powder (19mg, 30%). LCMS (ES) [M+1]⁺ m/z 440.1.

Example 88 Synthesis ofN-[(1S)-1-cyclopropylethyl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and (S)-1-cyclopropylethan-1-amine, following aprocedure similar as described above in Example 5. The crude reactionmixture was filtered and subjected to purification on reverse phasepreparative HPLC (Prep-C18, 5 μM SunFire column, 19×150 mm, Waters;gradient elution of 10% MeCN in water to 20% MeCN in water over a 10 minperiod, where both solvents contain 0.1% FA) to provide the titlecompound as an off-white solid (36.2 mg, 14%). ¹H NMR (300 MHz, DMSO) δ8.14 (s, 0.4H), 7.00 (s, 1H), 6.95 (s, 1H), 5.91 (br, 1H), 4.14 (t,J=6.0 Hz, 2H), 3.83 (s, 3H), 3.81-3.76 (m, 1H), 3.33-3.23 (m, 6H),3.09-3.04 (m, 2H), 2.85-2.73 (m, 2H), 2.18-2.13 (m, 4H), 1.95-1.90 (m,4H), 1.26 (d, J=6.6 Hz, 3H), 1.09-1.01 (m, 1H), 0.49-0.33 (m, 3H),0.23-0.18 (m, 1H). LCMS (ES) [M+1]⁺ m/z 410.2.

Example 89 Synthesis ofN-[(1R)-1-cyclopropylethyl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and (R)-1-cyclopropylethan-1-amine, following aprocedure similar as described above in Example 5. The crude reactionmixture was filtered and subjected to purification on reverse phasepreparative HPLC (Prep-C18, 5 μM SunFire column, 19×150 mm, Waters;gradient elution of 10% MeCN in water to 20% MeCN in water over a 10 minperiod, where both solvents contain 0.1% FA) to provide the titlecompound as an off-white solid (43.2 mg, 17%). ¹H NMR (300 MHz, CD₃OD) δ7.45 (s, 1H), 7.19 (s, 1H), 4.31 (t, J=5.4 Hz, 2H), 3.98 (s, 3H),3.64-3.55 (m, 2H), 3.49 (t, J=7.2 Hz, 2H), 3.40-3.28 (m, 5H), 3.02-2.97(m, 2H), 2.39-2.32 (m, 4H), 2.15-2.10 (m, 4H), 1.45 (d, J=6.3 Hz, 3H),1.24-1.18 (m, 1H), 0.69-0.56 (m, 2H), 0.40-0.33 (m, 2H). LCMS (ES)[M+1]⁺ m/z 410.2.

Example 90 Synthesis of1-(3-{[8-methoxy-4-(5-methylfuran-3-yl)-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy}propyl)pyrrolidineformate

Step 1

Into a 250-mL round-bottom flask, was placed a mixture of methyl4-bromofuran-2-carboxylate (3.0 g, 14.63 mmol, 1.00 eq.), 1,4-dioxane(100 mL),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(11.1 g, 43.89 mmol, 3.00 eq.), KOAc (4.3 g, 43.89 mmol, 3.00 eq.) andPd(dppf)Cl₂ (534 mg, 0.73 mmol, 0.05 eq.). The resulting mixture wasstirred for 16 h at 90° C. under N₂. The mixture was cooled to at andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluted with ethyl acetate/petroleum ether (1/3) to provide methyl4-(tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-carboxylate (1.3 g, 35%)as a yellow solid. LCMS (ES) m/z 253.2 [M+1]⁺.

Step 2

Into a 100-mL round-bottom flask, was placed a mixture of methyl4-(tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-carboxylate (500 mg, 1.98mmol, 1.00 eq.), 1,4-dioxane (60 mL), water (10 mL),1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) (568.8 mg, 1.58 mmol, 0.80 eq.), Cs₂CO₃ (1.9 g, 5.94mmol, 3.00 eq.) and Pd(PPh₃)₄ (116 mg, 0.10 mmol, 0.05 eq.). Theresulting mixture was stirred for 3 h at 100° C. under N₂. The mixturewas cooled to rt and concentrated under vacuum. The residue was purifiedby a silica gel column eluted with dichloromethane/methanol (5/1) toprovide methyl4-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl]furan-2-carboxylate(335 mg, 37%) as a gray solid. LCMS (ES) m/z 451.2 [M+1]⁺.

Step 3

Into a stirring solution of methyl4-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl]furan-2-carboxylate(330 mg, 0.73 mmol, 1.00 eq.) in THF (20 mL) at 0° C. was added LiAH₄(56 mg, 1.46 mmol, 2.00 eq.). The resulting mixture was stirred for 1 hand then quenched with water (0.06 mL), followed by addition of 15%sodium hydroxide aqueous solution (0.06 mL) and water (0.18 mL) in turn.The mixture was stirred for 30 minutes and then filtered through a padof celite. The filter cake was washed with THF (2×10 mL). The combinedfiltrate was concentrated under vacuum to provide4-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl]furan-2-yl)methanol(220 mg, 71%) as a yellow solid. LCMS (ES) m/z 423.2 [M+1]⁺.

Step 4

Into a 50-mL round-bottom flask, was placed a mixture of(4-[8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl]furan-2-yl)methanol(220 mg, 0.52 mmol, 1.00 eq.), methanol (20 mL), concentrated hydrogenchloride solution (1.8 mL) and 10% Pd/C (30 mg). The resulting mixturewas degassed and purged with H₂ for several times and then stirred for30 min at rt. The crude reaction mixture was filtered and subjected toreverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150mm, Waters; gradient elution of 4% MeCN in water to 24% MeCN in waterover a 6 min period, where both solvents contain 0.05% FA) to providethe title compound as a yellow solid (29.9 mg, 9%). ¹H NMR (300 MHz,DMSO-d₆): δ 8.23 (s, 2H), 8.04 (s, 1H), 7.34 (s, 1H), 7.11 (s, 1H), 6.80(s, 1H), 4.20 (t, J=6.0 Hz, 2H), 3.93 (s, 3H), 3.26-3.13 (m, 4H),2.87-2.78 (m, 6H), 2.35 (s, 3H), 2.28-2.21 (m, 2H), 2.18-2.05 (m, 2H),1.80-1.72 (m, 4H). LCMS (ES) m/z 407.2 [M+1]⁺.

Example 91 Synthesis ofN-butyl-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-4) and 1-butanamine, following a procedure similar asdescribed in Example 3 above. The reaction mixture was filtered andconcentrated and the crude dissolved in dimethylsulfoxide and subjectedto purification on reverse phase preparative HPLC (Prep-C18 XSelect, 5μM column, 19×150 mm, Waters; gradient elution of 0-50%% MeCN in waterover a 20 min period, where both solvents contain 0.1% formic acid) toprovide the title compound as a white powder (19 mg, 30%). LCMS (ES)[M+1]⁺ m/z 426.1.

Example 92 Synthesis of7-[3-(dimethylamino)propoxy]-8-methoxy-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from[3-([4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy)propyl]dimethylamine(Intermediate III-13) and propan-2-amine, following a procedure similaras described above in Example 5. The crude reaction mixture was filteredand subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM SunFire column, 19×150 mm, Waters; gradient elution of2% MeCN in water to 19% MeCN in water over a 6 min period, where bothsolvents contain 0.1% formic acid) to provide the title compound as ayellow solid (98.9 mg, 25%). ¹H NMR (300 MHz, DMSO-d₆): 8.23 (s, 1H),7.01 (s, 1H), 6.93 (s, 1H), 5.72 (d, J=7.8 Hz, 1H), 4.43-4.32 (m, 1H),4.09 (t, J=6.3 Hz, 2H), 3.82 (s, 3H), 3.05 (t, J=7.2 Hz, 2H), 2.79-2.70(m, 4H), 2.42 (s, 6H), 2.19-2.11 (m, 2H), 2.05-1.97 (m, 2H), 1.20 (d,J=6.6 Hz, 6H). LCMS (ES) [M+1]⁺ m/z 358.2.

Example 93 Synthesis of7-[3-(diethylamino)propoxy]-8-methoxy-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from[3-([4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy)propyl]diethylamine(Intermediate III-14) and propan-2-amine, following a procedure similaras described above in Example 5. The crude reaction mixture was filteredand subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μm XBridge column, 19×150 mm, Waters; gradient elution of2% MeCN in water to 18% MeCN in water over a 6 min period, where bothsolvents contain 0.1% formic acid) to provide the title compound as ayellow solid (76.3 mg, 21%). ¹H NMR (300 MHz, DMSO-d₆): 8.21 (s, 1H),6.99 (s, 1H), 6.92 (s, 1H), 5.70 (d, J=8.1 Hz, 1H), 4.43-4.32 (m, 1H),4.09 (t, J=6.3 Hz, 2H), 3.82 (s, 3H), 3.07-3.02 (m, 2H), 2.79-2.58 (m,8H), 2.18-2.09 (m, 2H), 1.94-1.90 (m, 2H), 1.20 (d, J=6.6 Hz, 6H), 1.02(t, J=6.9 Hz, 6H). LCMS (ES) [M+1]⁺ m/z 386.3.

Example 94 Synthesis ofN-tert-butyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and 2-methylpropan-2-amine, following a proceduresimilar as described above in Example 6 above, except that the reactionsolution was allowed to stir at 50° C. under N₂ atmosphere for 3 h. Thecrude reaction mixture was filtered and subjected to reverse phasepreparative HPLC (Prep-C18, 5 μM SunFire column, 19×150 mm, Waters;gradient elution of 5% MeCN in water to 40% MeCN in water over a 7 minperiod, where both solvents contain 0.1% FA) to provide the titlecompound as a gray solid (22.5 mg, 13%). ¹H NMR (300 MHz, DMSO-d₆) δ8.23 (s, 1H), 7.00 (s, 1H), 6.92 (s, 1H), 5.05 (s, 1H), 4.09 (t, J=6.3Hz, 2H), 3.82 (s, 3H), 3.05 (t, J=7.5 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H),2.67 (t, J=7.2 Hz, 2H), 2.62-2.59 (m, 4H), 2.17-2.08 (m, 2H), 2.01-1.95(m, 2H), 1.77-1.72 (m, 4H), 1.51 (s, 9H). LCMS (ES) [M+1]⁺ m/z 398.2.

Example 95 Synthesis ofN-isobutyl-8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-4) and 2-methyl-1-propanamine, following a proceduresimilar as described in Example 3 above. The reaction mixture wasfiltered and concentrated under reduced pressure. The residue wasdissolved in dimethylsulfoxide and subjected to purification on reversephase preparative HPLC (Prep-C18 XSelect, 5 μM column, 19×150 mm,Waters; gradient elution of 0-50% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid) to provide the titlecompound as a white powder (29 mg, 40%). LCMS (ES) [M+1]⁺ m/z 426.1.

Example 96 Synthesis ofN-(cyclobutylmethyl)-8-methoxy-2,2-dimethyl-7-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-4) and cyclobutylmethanamine, following a proceduresimilar as described in Example 3 above. The reaction mixture wasfiltered and concentrated under reduced pressure. The residue wasdissolved in dimethylsulfoxide and subjected to purification on reversephase preparative HPLC (Prep-C18 XSelect, 5 μM column, 19×150 mm,Waters; gradient elution of 0-50% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid) to provide the titlecompound as a white powder (15 mg, 20%). LCMS (ES) [M+1]⁺ m/z 438.1.

Example 97 Synthesis ofN-(cyclopropylmethyl)-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-4) and cyclopropyllmethanamine, following a proceduresimilar as described in Example 3 above. The reaction mixture wasfiltered and concentrated under reduced pressure. The residue wasdissolved in dimethylsulfoxide and subjected to purification on reversephase preparative HPLC (Prep-C18 XSelect, 5 μM column, 19×150 mm,Waters; gradient elution of 0-50%% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid) to provide the titlecompound as a white powder (24 mg, 33%). LCMS (ES) [M+1]⁺ m/z 424.1.

Example 98 Synthesis of1-(3-{[8-methoxy-4-(oxolan-3-yl)-1H,2H,3H-cyclopenta[c]quinolin-7-yl]oxy}propyl)pyrrolidineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,following a procedure similar as described above in Example 77 above,except that reaction solution was allowed to stir at 80° C. under N₂atmosphere overnight. The crude reaction mixture was filtered andsubjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridgecolumn, 19×150 mm, Waters; gradient elution of 5% MeCN in water to 15%MeCN in water over a 7 min period, where both solvents contain 0.1%formic acid) to provide the title compound as a light yellow solid (64.1mg, 27%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.21 (s, 1H), 7.31 (s, 1H), 7.09(s, 1H), 4.17 (t, J=6.3 Hz, 2H), 4.10 (t, J=7.8 Hz, 1H), 3.99-3.94 (m,1H), 3.91 (s, 3H), 3.89-3.82 (m, 2H), 3.74-3.66 (m, 1H), 3.19 (t, J=7.5Hz, 2H), 3.08-3.03 (m, 2H), 2.77-2.67 (m, 6H), 2.36-2.16 (m, 4H),2.04-1.98 (m, 2H), 1.79-1.76 (m, 4H). LCMS (ES) [M+1]⁺ m/z 397.2.

Example 99 Synthesis ofN-[(2S)-butan-2-yl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and (S)-butan-2-amine, following a procedure similaras described above in Example 5. The crude reaction mixture was filteredand subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of10% MeCN in water to 10% MeCN in water over a 7 min period, where bothsolvents contain 0.1% formic acid) to provide the title compound (32.3mg, 13%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (s, 1H),7.03 (s, 1H), 6.94 (s, 1H), 5.72 (d, J=8.1 Hz, 1H), 4.26-4.19 (m, 1H),4.14 (t, J=6.0 Hz, 2H), 3.83 (s, 3H), 3.17-3.14 (m, 6H), 3.06 (t, J=7.5Hz, 2H), 2.79-2.73 (m, 2H), 2.00-2.10 (m, 4H), 1.91-1.88 (m, 4H),1.68-1.47 (m, 2H), 1.17 (d, J=6.3 Hz, 3H), 0.90 (t, J=7.5 Hz, 3H). LCMS(ES) [M+1]⁺ m/z: 398.4.

Example 100 Synthesis ofN-[(2R)-butan-2-yl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and (R)-butan-2-amine, following a procedure similaras described above in Example 5. The crude reaction mixture was filteredand subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of10% MeCN in water to 20% MeCN in water over a 7 min period, where bothsolvents contain 0.1% formic acid) to provide the title compound (29.3mg, 12%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (s, 1H),7.03 (s, 1H), 6.95 (s, 1H), 5.74 (d, J=7.8 Hz, 1H), 4.26-4.19 (m, 1H),4.15 (t, J=6.3 Hz, 2H), 3.83 (s, 3H), 3.28-3.15 (m, 6H), 3.06 (t, J=7.5Hz, 2H), 2.83-2.72 (m, 2H), 2.17-2.06 (m, 4H), 1.93-1.84 (m, 4H),1.68-1.47 (m, 2H), 1.17 (d, J=6.6 Hz, 3H), 0.90 (t, J=7.5 Hz, 3H). LCMS(ES) [M+1]⁺ m/z: 398.4.

Example 101 Synthesis ofN-(2,2-dimethylpropyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and 2,2-dimethylpropan-1-amine, following aprocedure similar as described above in Example 5. The crude reactionmixture was filtered and subjected to purification on reverse phasepreparative HPLC (Prep-C18, 5 μM X Bridge column, 19×150 mm, Waters;gradient elution of 17% MeCN in water to 30% MeCN in water over a 6 minperiod, where both solvents contain 0.1% formic acid) to provide thetitle compound (82.5 mg, 30%) as brown oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.20 (s, 2H), 6.98 (s, 1H), 6.92 (s, 1H), 5.74 (t, J=6.0 Hz, 1H), 4.10(t, J=6.6 Hz, 2H), 3.82 (s, 3H), 3.36-3.34 (m, 2H), 3.09-3.03 (m, 2H),2.84-2.80 (m, 2H), 2.79-2.68 (m, 6H), 2.20-2.13 (m, 2H), 2.08-2.02 (m,2H), 1.83-1.75 (m, 4H), 0.94 (s, 9H). LCMS (ES) [M+1]⁺ m/z 412.3.

Example 102 Synthesis of8-methoxy-N-[(2-²H)propan-2-yl]-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminehydrochloride

Step 1

Into a 50-mL 3-necked round-bottom flask, was placed a mixture oflithio(deuterium)-5-alumane (287.7 mg, 6.85 mmol, 0.50 eq.) intetrahydrofuran (30 mL). To the mixture was addedN-(propan-2-ylidene)hydroxylamine (1.0 g, 13.68 mmol, 1.00 eq.)dropwise. The resulting solution was stirred for 4 h at 70° C. Aftercooled to 0° C., the reaction was quenched by addition of sodium sulfatedecahydrate (2.0 g). The product was purified by distillation at 1.0atmosphere, and the fractions at 40-60° C. was collected as the desiredproduct. This desired fractions was dissolved in a solution of1,4-dioxane (5 mL) that freshly saturated with HCl gas. The resultingmixture was allowed to stir at rt for 15 min, concentrated under vacuumto give (2-deuterium)propan-2-amine hydrogen chloride as a yellow solid(320 mg, 24%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.14 (br, 2H), 1.19 (s, 6H).

Step 2

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and (2-deuterium)propan-2-amine hydrogen chloride,following a procedure similar as described above in Example 5. The crudereaction mixture was filtered and subjected to purification on reversephase preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm,Waters; gradient elution of 20% MeCN in water to 31% MeCN in water overa 9 min period, where both solvents contain 0.05% TFA) to provide thetitle compound (44.8 mg, 4%) as a yellow semi-solid. ¹H NMR (300 MHz,DMSO-d₆): δ 8.26 (s, 2H), 7.01 (s, 1H), 6.93 (s, 1H), 5.72 (s, 1H), 4.11(t, J=6.3 Hz, 2H), 3.82 (s, 3H), 3.05 (t, J=7.2 Hz, 2H), 2.92-2.86 (m,6H), 2.79-2.74 (m, 2H), 2.18-2.02 (m, 4H), 1.85-1.77 (m, 4H), 1.20 (s,6H). LCMS (ES) [M+1]⁺ m/z 385.2.

Example 103 Synthesis of8-methoxy-N-(2-methylpropyl)-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and 2-methylpropan-1-amine, following a proceduresimilar as described above in Example 5. The crude reaction mixture wasfiltered and subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of10% MeCN in water to 35% MeCN in water over a 7.5 min period, where bothsolvents contain 0.1% trifluoroacetic acid) to provide the titlecompound (179.7 mg, 52%) as a light yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 12.56 (s, 1H), 9.77 (br, 1H), 8.49 (br, 1H), 7.63 (s, 1H),7.20 (s, 1H), 4.19 (t, J=5.7 Hz, 2H), 3.91 (s, 3H), 3.65-3.60 (m, 2H),3.39-3.30 (m, 4H), 3.27-3.22 (m, 2H), 3.10-2.98 (m, 2H), 2.94-2.89 (m,2H), 2.27-2.15 (m, 4H), 2.06-1.98 (m, 3H), 1.91-1.85 (m, 2H), 0.97 (d,J=6.6 Hz, 6H). LCMS (ES) [M+1]⁺ m/z: 398.2.

Example 104 Synthesis of8-methoxy-N-propyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and propan-1-amine, following a procedure similar asdescribed above in Example 5. The crude reaction mixture was filteredand subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of10% MeCN in water to 34% MeCN in water over a 7.5 min period, where bothsolvents contain 0.1% trifluoroacetic acid) to provide the titlecompound (126.7 mg, 37%) as a light yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 12.54 (s, 1H), 9.80 (br, 1H), 8.53 (t, J=5.4 Hz, 1H), 7.63(s, 1H), 7.20 (s, 1H), 4.18 (t, J=5.7 Hz, 2H), 3.91 (s, 3H), 3.65-3.59(m, 2H), 3.56-3.47 (m, 2H), 3.37-3.30 (m, 2H), 3.26-3.21 (m, 2H),3.10-3.02 (m, 2H), 2.92-2.87 (m, 2H), 2.24-2.17 (m, 4H), 2.08-1.95 (m,2H), 1.91-1.85 (m, 2H), 1.73-1.67 (m, 2H), 0.98 (t, J=6.9 Hz, 3H). LCMS(ES) [M+1]⁺ m/z: 384.2.

Example 105 Synthesis ofN-cyclopropyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and cyclopropanamine, following a procedure similaras described above in Example 5. The crude reaction mixture was filteredand subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of10% MeCN in water to 30% MeCN in water over a 7 min period, where bothsolvents contain 0.1% trifluoroacetic acid) to provide the titlecompound (122.0 mg, 36%) as a light yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 12.63 (s, 1H), 9.83 (br, 1H), 8.89 (s, 1H), 7.78 (s, 1H),7.23 (s, 1H), 4.21 (t, J=5.7 Hz, 2H), 3.92 (s, 3H), 3.66-3.58 (m, 2H),3.38-3.30 (m, 2H), 3.23-3.18 (m, 2H), 3.13-3.02 (m, 2H), 2.92-2.84 (m,3H), 2.25-2.15 (m, 4H), 2.08-1.96 (m, 2H), 1.95-1.87 (m, 2H), 1.07-1.01(m, 2H), 0.82-0.77 (m, 2H). LCMS (ES) [M+1]⁺ m/z: 382.2.

Example 106 Synthesis ofN-ethyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and ethanamine, following a procedure similar asdescribed above in Example 5. The crude reaction mixture was filteredand subjected to purification on reverse phase preparative HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of10% MeCN in water to 35% MeCN in water over a 7.5 min period, where bothsolvents contain 0.1% trifluoroacetic acid) to provide the titlecompound (94.7 mg, 29%) as a light yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 12.41 (s, 1H), 9.69 (br, 1H), 8.54 (br, 1H), 7.61 (s, 1H),7.21 (s, 1H), 4.18 (t, J=6.0 Hz, 2H), 3.91 (s, 3H), 3.65-3.54 (m, 4H),3.37-3.30 (m, 2H), 3.27-3.21 (m, 2H), 3.13-3.02 (m, 2H), 2.92-2.86 (m,2H), 2.26-2.17 (m, 4H), 2.08-2.05 (m, 2H), 1.92-1.85 (m, 2H), 1.29 (t,J=6.9 Hz, 3H). LCMS (ES) [M+1]⁺ m/z: 370.2.

Example 107 Synthesis ofN-cyclohexyl-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and cyclohexanamine, following a procedure similaras described above in Example 6 above, except that reaction solution wasallowed to stir at 100° C. under N₂ atmosphere for 2 h. The crudereaction mixture was filtered and subjected to reverse phase preparativeHPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elutionof 10% MeCN in water to 36% MeCN in water over a 9 min period, whereboth solvents contain 0.05% TFA) to provide the title compound (358.1mg, 73%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.69 (s, 1H), 9.86(br, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.65 (s, 1H), 7.19 (s, 1H), 4.19 (t,J=5.7 Hz, 2H), 4.07-4.05 (m, 1H), 3.91 (s, 3H), 3.65-3.63 (m, 2H),3.37-3.35 (m, 2H), 3.23-3.20 (m, 2H), 3.12-3.02 (m, 2H), 2.91 (t, J=7.5Hz, 2H), 2.27-2.20 (m, 4H), 2.05-1.87 (m, 6H), 1.82-1.78 (m, 2H),1.71-1.68 (m, 1H), 1.51-1.39 (m, 4H), 1.20-1.11 (m, 1H). LCMS (ES)[M+1]⁺ m/z 424.4.

Example 108 Synthesis ofN-(cyclopropylmethyl)-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and cyclopropylmethanamine, following a proceduresimilar as described above in Example 121. The crude reaction mixturewas filtered and subjected to reverse phase preparative HPLC (Prep-C18,5 μM XBridge column, 19×150 mm, Waters; gradient elution of 10% MeCN inwater to 36% MeCN in water over a 9 min period, where both solventscontain 0.05% TFA) to provide the title compound (289.4 mg, 59%) as awhite solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.67 (s, 1H), 10.06 (s, 1H),8.69 (t, J=5.4 Hz, 1H), 7.67 (s, 1H), 7.18 (s, 1H), 4.18 (t, J=5.7 Hz,2H), 3.90 (s, 3H), 3.66-3.63 (m, 2H), 3.49-3.44 (m, 2H), 3.37-3.35 (m,2H), 3.23 (t, J=7.5 Hz, 2H), 3.10-3.07 (m, 2H), 2.91 (t, J=6.9 Hz, 2H),2.24-2.21 (m, 4H), 2.05-2.00 (m, 2H), 1.95-1.87 (m, 2H), 1.25-1.16 (m,1H), 0.57-0.52 (m, 2H), 0.39-0.33 (m, 2H). LCMS (ES) [M+1]⁺ m/z 396.4.

Example 109 Synthesis of1-[3-({4-cyclopentyl-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,following a procedure similar as described above in Example 77 above,except that reaction solution was allowed to stir at 80° C. under N₂atmosphere for 5 h. The crude reaction mixture was filtered andsubjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridgecolumn, 19×150 mm, Waters; gradient elution of 5% MeCN in water to 25%MeCN in water over a 7.5 min period, where both solvents contain 0.1%formic acid) to provide the title compound (143.7 mg, 64%) as a lightyellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.23 (s, 1H), 7.29 (s, 1H),7.07 (s, 1H), 4.17 (t, J=6.3 Hz, 2H), 3.90 (s, 3H), 3.38-3.27 (m, 1H),3.18 (t, J=7.5 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.82-2.73 (m, 6H),2.23-2.15 (m, 2H), 2.08-1.93 (m, 6H), 1.83-1.65 (m, 8H). LCMS (ES)[M+1]⁺ m/z 395.2.

Example 110 Synthesis of1-[3-({4-cyclohexyl-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidinetrifluoroacetate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) and2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,following a procedure similar as described above in Example 77 above,except that the reaction solution was allowed to stir at 100° C. underN₂ atmosphere for 2 h. The crude product was purified by reverse phasepreparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters;gradient elution of 10% MeCN in water to 35% MeCN in water over a 9.5min period, where both solvents contain 0.1% TFA) to provide the titlecompound (121.6 mg, 30%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ9.97 (br, 1H), 7.87 (s, 1H), 7.41 (s, 1H), 4.28 (t, J=5.7 Hz, 2H), 4.00(s, 3H), 3.67-3.62 (m, 2H), 3.48-3.43 (m, 2H), 3.38-3.31 (m, 2H),3.25-3.20 (m, 2H), 3.13-3.04 (m, 3H), 2.33-2.24 (m, 4H), 2.10-2.04 (m,2H), 1.92-1.75 (m, 9H), 1.46-1.31 (m, 3H). LCMS (ES) [M+1]⁺ m/z 409.3.

Example 111 Synthesis of1-[3-({8-methoxy-4-phenyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidineformate

Into a 25-mL round-bottom flask, was placed1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate II-1) 1 (200 mg, 0.55 mmol, 1.00 eq.), 1,4-dioxane (5 mL),water (0.5 mL), phenylboronic acid (101 mg, 0.83 mmol, 1.50 eq.),potassium carbonate (153 mg, 1.11 mmol, 2.00 eq.) and Pd(PPh₃)₄ (64 mg,0.06 mmol, 0.10 eq.). The mixture was degassed under vacuum and purgedwith N₂ several times. The resulting solution was allowed to stir at110° C. under N₂ for 2 h. The crude reaction mixture was filtered andsubjected to reverse preparative HPLC (Prep-C18, 20-45 μM, 120 g,Tianjin Bonna-Agela Technologies; gradient elution of 15% MeCN in waterto 15% MeCN in water over a 5 min period, 15% MeCN in water to 30% MeCNin water over another 8 min period, where both solvents contain 0.1%formic acid) to provide the title compound (68.7 mg, 28%) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.87 (d, J=6.9 Hz, 2H),7.57-7.44 (m, 3H), 7.42 (s, 1H), 7.16 (s, 1H), 4.19 (t, J=6.6 Hz, 2H),3.95 (s, 3H), 3.30-3.17 (m, 4H), 2.67 (t, J=6.9 Hz, 2H), 3.63-3.55 (m,4H), 2.21 (t, J=7.2 Hz, 2H), 2.02 (t, J=7.2 Hz, 2H), 1.75-1.70 (m, 4H).LCMS (ES) [M+1]⁺ m/z: 403.1.

Example 112 Synthesis of8-methoxy-7-[3-(morpholin-4-yl)propoxy]-N-(propan-2-yl)-1H,2H,3H-cyclopenta[c]quinolin-4-aminetrifluoroacetate

The title compound was made from 4-[3-([4-chloro-8-methoxy-1H, 2H,3H-cyclopenta[c]quinolin-7-yl]oxy)propyl]morpholine (IntermediateIII-15) and propan-2-amine, following a procedure similar as describedabove in Example 5. The crude reaction mixture was filtered andsubjected to reverse phase preparative HPLC (Prep-C18, 5 μM, X Bridgecolumn, 19×150 mm, Waters; gradient elution of 4% MeCN in water to 24%MeCN in water over a 6 min period, where both solvents contain 0.05%TFA) to provide the title compound (251.4 mg, 38%) as a brown oil. ¹HNMR (300 MHz, DMSO-d₆) δ 12.41 (br, 1H), 9.91 (br, 1H), 8.18 (d, J=8.7Hz, 1H), 7.63 (s, 1H), 7.21 (s, 1H), 4.41-4.25 (m, 1H), 4.19 (t, J=5.7Hz, 2H), 4.12-3.96 (m, 2H), 3.91 (s, 3H), 3.72-3.60 (m, 2H), 3.60-3.46(m, 2H), 3.30-3.28 (m, 2H), 3.26-3.21 (m, 2H), 3.20-3.01 (m, 2H),2.93-2.88 (m, 2H), 2.31-2.14 (m, 4H), 1.34 (d, J=6.9 Hz, 6H). LCMS (ES)[M+1]⁺ m/z 400.2.

Example 113 Synthesis of1-[3-({4-cyclopentyl-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidinehydrochloride

A solution of1-(3-{[4-(cyclopent-1-en-1-yl)-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl]oxy}propyl)pyrrolidine(Example 83, 110.00 mg; 0.26 mmol; 1.00 eq.) in methanol (5.50 mL) waspurged with nitrogen. Palladium on carbon (2.78 mg; 0.03 mmol; 0.10 eq.)was added to the solution and the flask was purged with nitrogen onceagain. The flask was filled with hydrogen and the reaction mixture wasallowed to stir under a hydrogen atmosphere at rt overnight. The crudereaction mixture was filtered over celite and subjected to purificationon reverse phase preparative HPLC (Prep-C18 XSelect, 5 μM column, 19×150mm, Waters; gradient elution of 0-50% MeCN in water over a 20 minperiod, where both solvents contain 0.1% hydrochloric acid) to providethe title compound (88 mg, 80%). LCMS (ES) [M+1]⁺ m/z 424.1.

Example 114 Synthesis of1-[3-({8-methoxy-2,2-dimethyl-4-phenyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)propyl]pyrrolidineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-pyrrolo[3,2-c]quinolin-7-yl}oxy)-propyl]pyrrolidine(Intermediate III-2) and phenylboronic acid, following a proceduresimilar as described above in Example 83. The volatiles were removedunder reduced pressure and the residue was redissolved in DMSO, filteredand subjected to purification on reverse phase preparative HPLC(Prep-C18 XSelect, 5 μM column, 19×150 mm, Waters; gradient elution of10-50% MeCN in water over a 20 min period, where both solvents contain0.1% hydrochloric acid) to provide the title compound as a yellow solid.LCMS (ES) [M+1]⁺ m/z 432.1.

Example 115 Synthesis ofN-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta-[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and (2,4-dimethoxyphenyl)methanamine, following aprocedure similar as described in Example 3 above, except that reactionmixture was allowed to stir at 140° C. under N₂ for 1.5 h. The crudemixture was treated with water and the volatiles were removed underreduced pressure. The residue were redissolved in DMSO, filtered andsubjected to reverse phase preparative HPLC (Prep-C18, 5 μM XBridgecolumn, 19×150 mm, Waters; gradient elution of 0-40% MeCN in water overa 20 min period, where both solvents contain 0.1% formic acid (FA)) toprovide the title compound as a white solid. LCMS (ES) [M+1]⁺ m/z 492.1.

Example 116 Synthesis of8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

A mixture ofN-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate (Example 115, 228 mg, 0.46 mmol) in TFA (0.5 mL) and CHCl₃ (0.8mL) was allowed to stir at 70° C. for 1.5 hr. The organic volatiles wereremoved under reduced pressure, and the residues were dissolved in DMSO,filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μMXBridge column, 19×150 mm, Waters; gradient elution of 0-40% MeCN inwater over a 20 min period, where both solvents contain 0.1% formic acid(FA)) to provide the title compound as a white solid. LCMS (ES) [M+1]⁺m/z 342.1.

Example 117 Synthesis ofN-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-2,2-dimethyl-1H,2H,3H-cyclopenta[c]quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-4) and (2,4-dimethoxyphenyl)methanamine, following aprocedure similar as described above in Example 115. The crude mixturewas treated with water and the volatiles were removed under reducedpressure. The residue were redissolved in DMSO, filtered and subjectedto reverse phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150mm, Waters; gradient elution of 0-40% MeCN in water over a 20 minperiod, where both solvents contain 0.1% formic acid (FA)) to providethe title compound as a white solid. LCMS (ES) [M+1]⁺ m/z 520.1.

Example 118 Synthesis of8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made fromN-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-2,2-dimethyl-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate (Example 117) following a procedure similar as described abovein Example 116. The crude mixture was treated with water and thevolatiles were removed under reduced pressure. The organic volatileswere removed from the crude reaction mixture under reduced pressure, andthe residues were dissolved in DMSO, filtered and subjected to reversephase preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm,Waters; gradient elution of 0-40% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid (FA)) to provide the titlecompound as a white solid. LCMS (ES) [M+1]⁺ m/z 370.1.

Example 119 Synthesis of3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)propanenitrileformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and 3-aminopropanenitrile, (2E)-but-2-enedioicacetate, following a procedure similar as described in Example 3 above,except that BuONa was used in 10.0 equivalents. The crude product wastreated with water and the organic volatiles were removed under reducedpressure. The residues were re-dissolved in DMSO, filtered and subjectedto reverse phase preparative HPLC (Prep-C18, 5 μM OBD column, 19×250 mm,waters; gradient elution of 0-25% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) toprovide the title compound as a brown syrup. LCMS (ES) [M+1]⁺ m/z 395.2.

Example 120 Synthesis of8-methoxy-N-[2-(methylsulfanyl)ethyl]-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-amineformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and 2-(methylsulfanyl)ethanamine, following aprocedure similar as described above in Example 3, except that reactionmixture was allowed to stir at 140° C. under N₂ for 1.5 h. The crudeproduct was treated with water and the organic volatiles were removedunder reduced pressure. The residues were re-dissolved in DMSO, filteredand subjected to reverse phase preparative HPLC (Prep-C18, 5 μM OBDcolumn, 19×250 mm, waters; gradient elution of 0-40% MeCN in water overa 20 min period, where both solvents contain 0.1% formic acid, flowrate: 20 mL/min) to provide the title compound as a light yellow solid.LCMS (ES) [M+1]⁺ m/z 416.2.

Example 121 Synthesis of(1S,3R)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-oland(1R,3S)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-ol(1:1 Mixture in Form of formate Salt) and(1R,3R)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-olformate and(1S,3S)-3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-ol(1:1 Mixture in Form of Formate Salt)

The title compounds as two pairs of 1:1 mixture in form of formate salt,were made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and 3-aminocyclohexanol, following a proceduresimilar as described above in Example 3, except that reaction mixturewas allowed to stir at 140° C. under N₂ for 1.5 h. The crude product wastreated with water and the organic volatiles were removed under reducedpressure. The residues were re-dissolved in DMSO, filtered and subjectedto reverse phase preparative HPLC (Prep-C18, 5 μM OBD column, 19×250 mm,waters; gradient elution of 0-25% MeCN in water over a 20 min period,where both solvents contain 0.1% formic acid, flow rate: 20 mL/min) toprovide two fractions with desired mass of LCMS (ES) [M+1]⁺ m/z 440.2.Among them, the fraction came out of the column first was a 1:1 mixtureof two isomers, LCMS (ES) [M+1]⁺ m/z 440.2, which was one of two titledmixtures; the fraction came out of the column second was a 1:1 mixtureof two isomers, LCMS (ES) [M+1]⁺ m/z 440.2, which was the other of twotitled mixtures.

Example 122 Synthesis of(1S,2S)-2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-olformate

The title compounds was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and (1R,2R)-2-aminocyclohexanol, following aprocedure similar as described above in Example 3, except that thereaction mixture was allowed to stir at 130° C. under N₂ for 1.5 h. Thecrude product was treated with water and the organic volatiles wereremoved under reduced pressure. The residues were re-dissolved in DMSO,filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μMOBD column, 19×250 mm, waters; gradient elution of 0-25% MeCN in waterover a 20 min period, where both solvents contain 0.1% formic acid, flowrate: 20 mL/min) to provide the title compound as a white solid. LCMS(ES) [M+1]⁺ m/z 440.2.

Example 123 Synthesis of(1R,4R)-4-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclohexan-1-olformate

The title compounds was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and trans-4-aminocyclohexan-1-ol, following aprocedure similar as described above in Example 3, except that thereaction mixture was allowed to stir at 130° C. under N₂ for 1.5 h. Thecrude product was treated with water and the organic volatiles wereremoved under reduced pressure. The residues were re-dissolved in DMSO,filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μMOBD column, 19×250 mm, waters; gradient elution of 0-25% MeCN in waterover a 20 min period, where both solvents contain 0.1% formic acid, flowrate: 20 mL/min) to provide the title compound as a white solid. LCMS(ES) [M+1]⁺ m/z 440.2.

Example 124 Synthesis of(1S,25)-2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclopentan-1-olformate

The title compounds was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and (1R,2R)-2-aminocyclopentane-1-ol, following aprocedure similar as described above in Example 3, except that thereaction mixture was allowed to stir at 140° C. under N₂ for 1.5 h. Thecrude product was treated with water and the organic volatiles wereremoved under reduced pressure. The residues were re-dissolved in DMSO,filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μMOBD column, 19×250 mm, waters; gradient elution of 0-25% MeCN in waterover a 20 min period, where both solvents contain 0.1% formic acid, flowrate: 20 mL/min) to provide the title compound as a yellow solid. LCMS(ES) [M+1]⁺ m/z 426.1.

Example 125 Synthesis of(1R,2S)-2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclopentan-1-oland(1S,2R)-2-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclopentan-1-ol(1:1) mixture as formate salt

The title compounds, as a 1:1 mixture in form of formate salt, was madefrom1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and cis-2-aminocyclopentane-1-ol, following aprocedure similar as described above in Example 3, except that thereaction mixture was allowed to stir at 140° C. under N₂ for 1.5 h. Thecrude product was treated with water and the organic volatiles wereremoved under reduced pressure. The residues were re-dissolved in DMSO,filtered and subjected to reverse phase preparative HPLC (Prep-C18, 5 μMOBD column, 19×250 mm, waters; gradient elution of 0-25% MeCN in waterover a 20 min period, where both solvents contain 0.1% formic acid, flowrate: 20 mL/min) to provide the title compounds as a mixture as a yellowsolid. LCMS (ES) [M+1]⁺ m/z 426.1.

Example 126 Synthesis of3-({8-methoxy-7-[3-(pyrrolidin-1-yl)propoxy]-1H,2H,3H-cyclopenta[c]quinolin-4-yl}amino)cyclopentan-1-olformate

The title compound was made from1-[3-({4-chloro-8-methoxy-1H,2H,3H-cyclopenta[c]-quinolin-7-yl}oxy)propyl]pyrrolidine(Intermediate II-1) and 3-aminocyclopentane-1-ol following a proceduresimilar as described above in Example 3, except that the reactionmixture was allowed to stir at 140° C. under N₂ for 1.5 h. The crudeproduct was treated with water and the organic volatiles were removedunder reduced pressure. The residues were re-dissolved in DMSO, filteredand subjected to reverse phase preparative HPLC (Prep-C18, 5 μM OBDcolumn, 19×250 mm, waters; gradient elution of 0-25% MeCN in water overa 20 min period, where both solvents contain 0.1% formic acid, flowrate: 20 mL/min) to provide the title compound as a yellow solid. LCMS(ES) [M+1]⁺ m/z 426.1.

BIOLOGICAL EXAMPLES Example 1 Determination of G9a Enzymatic ActivityAssay

The G9a AlphaLISA assay was used to detect the methyl modifications of abiotinylated histone H3 peptide by the compounds. These modificationsare done by the histone methyl transferase activity of the G9a enzyme.The assay consists of reading a chemiluminescent signal at 615 nm; thissignal is generated by a laser excitation at 680 nm that transfers areactive singlet oxygen between the donor beads and acceptor beads.Donor beads are streptavidin conjugated and bind to the biotin on thepeptide. Acceptor beads are conjugated with an antibody that recognizesthe specific G9a methyl mark on the peptide. If there is a methyl markon the peptide, the acceptor beads will bind to the peptide. Uponbinding, the acceptor beads will be in close proximity (<200 nm) of thedonor beads and when the donor beads are excited, the transfer of theoxygen can occur and a strong signal will be generated. If there is nomethyl mark, the interaction between beads will not occur and signalwill be at background levels.

For the assay, the following buffer was used to set up reactions: 50 mMTris-HCl pH9, 50 mM NaCl, 0.01% Tween-20 and 1 mM DTT (added fresh priorto starting the reactions). The assay is set up by adding a finalconcentration of 0.15 nM G9a, 15 uM S-adenosyl-methionine and, 100 nMbiotinylated histone 3 peptide (1-21). The reaction is incubated at roomtemperature for 1 hour, and subsequently quenched by the addition of theacceptor beads (anti-H3k9me2 AlphaLISA acceptor beads, PerkinElmer #AL117) at a final concentration of 20 ug/mL. The acceptor beads areincubated for 1 hour. After 1 hour, the donor beads are added at a finalconcentration of 20 ug/mL (Alpha Streptavidin donor beads, PerkinElmer#6760002). Donor beads are incubated for 0.5 hours. Both donor andacceptor beads are resuspended in AlphaLISA 5X Epigenetics Buffer 1 Kit(PerkinElmer # AL008) prior to addition to the reaction. Allmanipulations and incubations with the donor and acceptor beads are donein subdued light. Signal is detected in an EnVision plate reader inAlpha mode (see ACS Med Chem Lett. 2014 Jan. 2; 5(2):205-9. doi:10.1021/m1400496h. eCollection 2014. Discovery and development of potentand selective inhibitors of histone methyltransferase g9a.)

Percent inhibition was calculated for each compound dilution and theconcentration that produced 50% inhibition was calculated. This value ispresented as the IC₅₀. The IC₅₀ values for a representative number ofcompounds of the disclosure are provided below.

TABLE A Cmpd No. (see Cmpd # in Table 1) G9a in (uM) 1 0.031 2 0.029 30.015 4 0.04 5 0.15 6 0.027 7 0.045 8 0.04 9 0.69 10 0.19 11 0.27 120.52 13 0.042 14 0.19 15 0.19 16 0.11 17 0.21 18 0.11 19 0.057 20 0.1421 0.62 22 0.003 23 0.003 24 0.006 25 0.005 26 0.004 27 0.006 28 0.00629 0.009 30 0.008 31 0.009 32 0.022 33 0.012 34 0.010 35 0.012 36 0.00937 1.3 38 3.0 39 3.0 40 1.3 41 0.50 42 0.52 43 1.70 44 5.8 45 4.3 460.26 47 3.1 48 0.97 49 0.046 50 0.24 51 0.88 52 0.34 53 0.043 54 0.04855 0.32 56 0.46 57 0.21 58 0.17 59 0.23 60 0.21 61 0.14 62 0.12 63 2.364 0.50 65 0.74 66 0.22 67 2.0 68 0.11 69 >10 70 0.19 71 1.1 72 0.69 731.9 74 0.015 75 0.014 76 0.013 77 0.007 78 0.003 79 0.003 80 0.009 810.009 82 0.006 83 0.009 84 1.60 85 0.66 86 >10.0 87 0.15 88 0.003 890.14 90 0.60 91 0.007 92 0.059 93 0.39 94 1.4 95 0.07 96 0.10 97 0.08498 >10.0 99 0.023 100 0.047 101 0.070 102 0.013 103 0.027 104 0.020 1050.021 106 0.013 107 0.016 108 0.037 109 0.50 110 1.4 111 4.9 112 >10 1130.006 114 0.17 115 0.009 116 0.006 117 0.36 118 0.018 119 0.11 120 0.075121 0.073 and 0.16 respectively 122 0.043 123 0.17 124 4.7 125 1.0 1260.15

Example 2 Fetal Hemoglobin Induction Assay

Cryopreserved bone marrow CD34⁺ hematopoietic cells obtained fromhealthy adult human donors were used for all studies. A 21 day ex vivoserum free culture system was utilized that consists of two phases. Inculture phase I (culture days 1-7), CD34⁺ cells were placed in mediacontaining StemPro-34 complete media (1-glutamine, pen-strep andStemPro-34 nutrient supplement) (Invitrogen, Carlsbad, Calif.)supplemented with 50 ng/ml SCF (HumanZyme, Chicago, Ill.), 50 ng/mlFLT3-Ligand (HumanZyme) and 10 ng/ml IL-3 (HumanZyme). During the firstphase of culture (days 0-7), the CD34⁺ cells differentiate intoprogenitor cell populations that include erythroblasts. After 7 days,the cells were transferred to erythropoietin (EPO; Stemcell)supplemented medium (phase 2; culture days 7-21) which is comprised ofthe following: StemPro-34 complete medium, 4 U/ml EPO, 3 μM mifepristone(Sigma Aldrich, St. Louis, Mo.), 10 μg/ml insulin (Sigma Aldrich), 3U/ml heparin (Sigma Aldrich) and 0.8 mg/ml holo transferrin (SigmaAldrich). The Compounds are added during phase 2; days 7-21 to testfetal hemoglobin production (see Blood. 2015 Jul. 30; 126(5):665-72.Inhibition of G9a methyltransferase stimulates fetal hemoglobinproduction by facilitating LCR/γ-globin looping).

Expression levels of α-, ⊕- and γ-globin genes are assessed byquantitative PCR analyses. HbF protein levels are assessed by the humanHemoglobin F enzyme-linked immunosorbent assay (ELISA) Quantitation Kit(Bethyl Laboratory, Montgomery, Tex., USA). Percentages of cellsexpressing HbF are assessed by flow cytometry analysis. In brief, RNAsamples were prepared and complementary DNA was synthesized, accordingto the manufacturer's instructions (Qiagen, Germany). The qRT-PCRanalysis of human globin genes was performed using the TaqMan GeneExpression Master.

Formulation Examples

The following are representative pharmaceutical formulations containinga compound of the present disclosure.

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Ingredient Quantity per tablet mg compound of this disclosure 400cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Ingredient Quantity per capsule mg compound of this disclosure 200lactose spray dried 148 magnesium stearate 2

Injectable Formulation

Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1% Tween 80 inDI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL

Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound disclosed herein is mixed with 50 mg of anhydrous citricacid and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound disclosed herein is mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and100 mL of purified alcohol USP. The resulting gel mixture is thenincorporated into containers, such as tubes, which are suitable fortopical administration.

Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound disclosed herein is mixed with 0.9 g of NaCl in 100 mL ofpurified water and filtered using a 0.2 micron filter. The resultingisotonic solution is then incorporated into ophthalmic delivery units,such as eye drop containers, which are suitable for ophthalmicadministration.

Nasal Spray Solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compounddisclosed herein is mixed with 30 mL of a 0.05M phosphate buffersolution (pH 4.4). The solution is placed in a nasal administratordesigned to deliver 100 μL of spray for each application.

What is claimed:
 1. A compound of Formula (I):

where: Z¹ is C; Z² is CH; X is C; alk is —O—(CH₂)₂₋₄*, wherein *indicates the point of attachment to —R¹; R¹ is unsubstitutedheterocyclyl or heterocyclyl substituted with 1 or 2 of R^(a) and R^(b)wherein R^(a) and R^(b) are independently alkyl or halo; R² is anunsubstituted C₁₋₄ alkoxy; wherein, -alk-R¹ is attached to carbon (a)and R² is attached to carbon (b); R³ is H; R⁴ is alkyl or NR^(e)R^(f)(where R^(e) is hydrogen or alkyl, and R^(f) is hydrogen, alkyl,deuterated alkyl, alkylthioalkyl, acyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, or heterocyclylalkyl), wherein the cycloalkyl, the aryl,the heteroaryl, and the heterocyclyl are independently unsubstituted orsubstituted with 1, 2, or 3 of R^(g), R^(h), and R^(i), wherein R^(g),R^(h), and R^(i) are independently selected from alkyl, hydroxy, alkoxy,halo, haloalkyl, cyano, carboxy, alkoxycarbonyl, and haloalkoxy; ring Bis unsubstituted 5- or 6-membered cycloalkyl or 5- or 6-memberedcycloalkyl substituted with 1, 2, 3, or 4 of R^(j), R^(k), R^(l), andR^(m) wherein R^(j), R^(k), R^(l), and R^(m) are independently selectedfrom alkyl, hydroxy, alkoxy, halo, haloalkyl, and haloalkoxy; or, ring Bis an unsubstituted 5-, 6-, or 7-membered saturated heterocyclyl or a5-, 6-, or 7-membered saturated heterocyclyl substituted with 1, 2, 3,or 4 of R^(j), R^(k), R^(l), and R^(m) wherein R^(j), R^(k), R^(l), andR^(m) are independently selected from alkyl, hydroxy, alkoxy, halo,haloalkyl, and haloalkoxy; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is NR^(e)R^(f) (where R^(e) is hydrogen oralkyl, and R^(f) is hydrogen, alkyl, acyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl), whereinthe cycloalkyl, the aryl, the heteroaryl, and the heterocyclyl isunsubstituted or substituted with 1, 2, or 3 of R^(g), R^(h), and R^(i)wherein R^(g), R^(h), and R^(i) are independently selected from alkyl,hydroxy, alkoxy, halo, haloalkyl, cyano, carboxy, alkoxycarbonyl, andhaloalkoxy.
 3. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein the compound, or a pharmaceutically acceptablesalt thereof, is selected from the group consisting of: 1

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or a parent compound of any of the salts shown above, or apharmaceutically acceptable salt of the parent compound.
 4. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable excipient.
 5. The compound of claim 3, or a pharmaceuticallyacceptable salt thereof, wherein the compound, or a pharmaceuticallyacceptable salt thereof, is selected from the group consisting of: 1

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or a parent compound of any of the salts shown above, or apharmaceutically acceptable salt of the parent compound.
 6. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein, alkis —O—(CH₂)₃*; R¹ is -pyrrolidin-1-yl; and R² is methoxy.
 7. Thecompound of claim 6, or a pharmaceutically acceptable salt thereof,wherein R⁴ is alkyl.
 8. The compound of claim 6, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is —NR^(e)R^(f).
 9. The compound ofclaim 8, or a pharmaceutically acceptable salt thereof, wherein R^(e) ishydrogen or alkyl, and R^(f) is alkyl.
 10. The compound of claim 9, or apharmaceutically acceptable salt thereof, wherein said alkyl of R^(e) orR^(f) is independently selected from the group consisting of methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and t-butyl. 11.The compound of claim 10, or a pharmaceutically acceptable salt thereof,wherein ring B is unsubstituted 5- or 6-membered cycloalkyl or 5- or6-membered cycloalkyl substituted with 1 or 2 of R^(j) and R^(k),wherein R^(j) and R^(k) are each independently alkyl, halo or hydroxy.12. The compound of claim 11, or a pharmaceutically acceptable saltthereof, wherein ring B is unsubstituted cyclopentyl or cyclopentylsubstituted with 1 or 2 of R^(j) and R^(k), wherein R^(j) and R^(k) areeach independently alkyl.
 13. The compound of claim 11, or apharmaceutically acceptable salt thereof, wherein ring B is cyclopentylor cyclohexyl.
 14. The compound of claim 13, or a pharmaceuticallyacceptable salt thereof, wherein ring B is cyclopentyl.
 15. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein ringB is a 5, 6 or 7 membered nitrogen containing heterocyclyl.
 16. Thecompound of claim 15, or a pharmaceutically acceptable salt thereof,wherein R⁴ is alkyl.